WO2007024705A2 - Procede de traitement de la depression au moyen d'un anticorps anti-tnf-alpha - Google Patents

Procede de traitement de la depression au moyen d'un anticorps anti-tnf-alpha Download PDF

Info

Publication number
WO2007024705A2
WO2007024705A2 PCT/US2006/032365 US2006032365W WO2007024705A2 WO 2007024705 A2 WO2007024705 A2 WO 2007024705A2 US 2006032365 W US2006032365 W US 2006032365W WO 2007024705 A2 WO2007024705 A2 WO 2007024705A2
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
depression
antigen
tnfα
binding portion
Prior art date
Application number
PCT/US2006/032365
Other languages
English (en)
Other versions
WO2007024705A3 (fr
Inventor
Rebecca S. Hoffman
Michael W. Decker
Ana M. Basso
Lynne E. Rueter
Walid M. Abi-Saab
Original Assignee
Abbott Biotechnology Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37772215&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2007024705(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbott Biotechnology Ltd. filed Critical Abbott Biotechnology Ltd.
Priority to EP06801876.1A priority Critical patent/EP1924287B1/fr
Publication of WO2007024705A2 publication Critical patent/WO2007024705A2/fr
Publication of WO2007024705A3 publication Critical patent/WO2007024705A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Patent Application Serial No. 10/623039 filed July 18, 2003; U.S. Patent Application Serial No. 10/623076, filed July 18, 2003; U.S. Patent Application Serial No. 10/623065, filed July 18, 2003; U.S. Patent Application Serial No. 10/622928, filed July 18, 2003; U.S. Patent Application Serial No. 10/623075, filed July 18, 2003; U.S. Patent Application Serial No. 10/623035, filed July 18, 2003; U.S. Patent Application Serial No. 10/622683, filed July 18, 2003; U.S. Patent Application Serial No. 10/622205, filed July 18, 2003; U.S. Patent Application Serial No. 10/622210, filed July 18, 2003; and U.S. Patent Application Serial No. 10/623318, filed July 18, 2003.
  • This application is also related to US Appln. No. 11/104117. The entire contents of each of these patents and patent applications are hereby incorporated herein by reference.
  • Depression including major depression, affects approximately 20-25% of women and 7-12% of men in Western countries at some point in their lifetime. Depression is the most common mental disease and the fourth most important cause of disability worldwide. It is expected that rates of depression in the population will increase in the future. Many patients remain undiagnosed and undertreated due to social stigma associated with psychiatric treatments, inappropriate training of general practitioners for the diagnosis of the disease, or low awareness between patients and doctors of depression as a treatable illness.
  • cytokines in depressed patients can be normalized after chronic antidepressant treatment with serotonin re-uptake inhibitors (SSRIs) (Tuglu et al. Psychopharmacology (Bed) 170, 429-33 (2003)).
  • SSRIs serotonin re-uptake inhibitors
  • the invention provides a method of treating depression based on the inhibition of peripheral cytokine activity, especially TNF ⁇ .
  • the present invention includes methods of treating depression comprising systemically administering a human TNF ⁇ antibody such that peripheral TNF ⁇ activity is inhibited.
  • the invention includes treatment of depression achieved through systemic administration of a TNF ⁇ inhibitor to a subject having depression.
  • the TNF ⁇ inhibitor used in the invention is etanercept.
  • the TNF ⁇ inhibitor used in the invention is a TNF ⁇ antibody, including infliximab, adalimumab, and golimumab.
  • the invention includes a method for treating depression comprising inhibiting TNF ⁇ activity in a subject suffering from depression by systemically administering to the subject a TNF ⁇ antibody, or an antigen-binding portion thereof, such that depression is treated.
  • the invention also provides a method for improving the mood of a subject having depression comprising systemically administering an TNF ⁇ antibody, or antigen- binding portion thereof, such that the mood of the subject having depression is improved.
  • the invention describes a method for treating depression in a subject having an increased level of serum TNF ⁇ comprising systemically administering to the subject an TNF ⁇ antibody, or antigen-binding portion thereof, such that the serum level of TNF ⁇ is decreased relative to pre-treatment levels.
  • Another aspect of the invention is a method of inhibiting peripheral TNF ⁇ activity in a subject suffering from depression comprising subcutaneously administering an TNF ⁇ antibody to said subject, such that peripheral TNF ⁇ activity is inhibited.
  • the invention also includes a method for treating TNF ⁇ - mediated depression in a subject suffering from said depression comprising systemically administering to the subject a TNF ⁇ antibody, or an antigen-binding portion thereof, such that the depression is treated.
  • the invention also includes a method of achieving a HAM-D score of ⁇ 7 in a subject having depression comprising systemically administering to the subject a TNF ⁇ antibody, or an antigen-binding portion thereof, such that the subject's HAM-D score is ⁇ 7.
  • the TNF ⁇ antibody, or an antigen-binding portion thereof is selected from the group consisting of infliximab, golimumab, and adalimumab. In one embodiment, the TNF ⁇ antibody, or an antigen-binding portion thereof, is a human antibody, or antigen-binding portion thereof.
  • the human antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K ⁇ of 1 x 10 " ⁇ M or less and a K o ff rate constant of 1 x 10 ⁇ 3 s ⁇ l or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10 ⁇ 7 M or less.
  • the human antibody, or antigen-binding portion thereof is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe-binding portion thereof.
  • the human TNF ⁇ antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K ⁇ of 1 x 10" ⁇ M or less and a K o ff rate constant of 1 x 10 ⁇ 3 s ⁇ ⁇ or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10 ⁇ 7 M or less.
  • the human TNF ⁇ antibody, or antigen-binding portion thereof has the following characteristics: a) dissociates from human TNF ⁇ with a K o ff rate constant of 1 x 10" 3 s -1 or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12; In still another embodiment, the human TNF ⁇ antibody, or antigen-binding portion thereof, comprises a light chain variable region (LC
  • the human TNF ⁇ antibody, or antigen-binding portion thereof is D2E7.
  • the methods of the invention may be used to treat major depression.
  • the major depression is a single episode.
  • the major depression is recurrent.
  • the major depression is refractory or treatment resistant depression.
  • the methods of the invention may also be used to treat depression which is a cyclothymic disorder.
  • the methods of the invention may also be used to treat depression selected from the group consisting of dysthmic disorder, bipolar disorder I, and bipolar disorder II.
  • the disorder occurs in combination with catatonic features, melancholic features, or with atypical features of postpartum depression.
  • systemic administration of the human TNF ⁇ antibody, or antigen-binding portion thereof is subcutaneous. In another embodiment, the systemic administration of the human TNF ⁇ antibody, or antigen-binding portion thereof, is peripheral. In another embodiment, the systemic administration is selected from the group consisting of subcutaneous administration, intraperitoneal administration, and intravenous administration. In one embodiment of the invention, the subject has an additional disorder associated with increased levels of TNF ⁇ . In one embodiment of the invention, the subject has an additional disorder which is a TNF ⁇ related disorder. In another embodiment, the subject has an additional disorder selected from the group consisting of coronary heart disease, a neurodegenerative disease, an autoimmune disease, an intestinal disorder, and an infectious disease. In one embodiment, the neurodegenerative disease is stroke.
  • the autoimmune disorder is selected from the group consisting of psoriasis, psoriatic arthritis, and rheumatoid arthritis.
  • the subject further has a disorder selected from the group consisting of Behcet's disease, asthma, and Niemann-Pick disease.
  • the intestinal disorder is inflammatory bowel disease or Crohn's disease.
  • the invention includes further administering an antidepressant agent to the subject in combination with a human TNF ⁇ , antibody, or antigen-binding portion thereof.
  • the human TNF ⁇ antibody, or antigen-binding portion thereof is administered on a biweekly dosing regimen.
  • the antibody is administered on dosing regimen selected from the group consisting of a biweekly dosing regimen, a multiple variable dose regimen, and a weekly dosing regimen.
  • the human TNF ⁇ antibody, or antigen-binding portion thereof is administered in a 40 mg dose.
  • kits containing a human TNF ⁇ antibody, or antigen- binding portion thereof, and instructions for administering the antibody to an affect The invention provides a kit comprising a packaging material; a TNF ⁇ antibody, or antigen-binding portion thereof; and a label or package insert contained within the packaging material indicating that the TNF ⁇ antibody, or antigen-binding portion thereof, may be used for the treatment of depression.
  • the package insert further contains instructions for systemic administration of the TNF ⁇ antibody, or antigen-binding portion thereof.
  • the package insert further contains instructions for subcutaneous administration of the TNF ⁇ antibody,, or antigen-binding portion thereof.
  • the TNF ⁇ antibody, or antigen-binding portion thereof comprises a dose of about 40 mg. In one embodiment, the TNF ⁇ antibody, or antigen-binding portion thereof, is selected from the group consisting of adalimumab, infliximab, and golimumab.
  • the human antibody dissociates from human TNF ⁇ with a K ⁇ of 1 x 10 ⁇ s M or less and a Karate constant of 1 x 10" 3 s "1 or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10 ⁇ 7 M or less.
  • human TNF ⁇ (abbreviated herein as hTNF ⁇ , or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 IcD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules.
  • hTNF ⁇ The structure of hTNF ⁇ is described further in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, J.M., et al (1987) Biochemistry 26: 1322-1326; and Jones, E.Y., et al. (1989) Nature 338:225-228.
  • human TNF ⁇ is intended to include recombinant human TNF ⁇ (rhTNF ⁇ ), which can be prepared by standard recombinant expression methods or purchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis, MN). TNF ⁇ is also referred to as TNF.
  • rhTNF ⁇ recombinant human TNF ⁇
  • TNF ⁇ is also referred to as TNF.
  • the term "TNF ⁇ inhibitor” refers to an agent which interferes with tumor necrosis factor alpha (TNF ⁇ ) activity.
  • the term also includes each of the anti- TNF ⁇ human antibodies and antibody portions described in U.S. Patent Nos. 6,090,382; 6,258,562; 6,509,015, and in U.S. Patent Application Serial Nos. 09/801185 and 10/302356, each of which is incorporated by reference herein.
  • the TNF ⁇ inhibitor used in the invention is an anti-TNF ⁇ antibody, or a fragment thereof, including infliximab (Remicade ® , Johnson and Johnson; described in U.S. Patent No.
  • CDP571 a humanized monoclonal anti- TNF-alpha IgG4 antibody
  • CDP 870 a humanized monoclonal anti-TNF-alpha antibody fragment
  • an anti-TNF dAb Peptech
  • CNTO 148 golimumab; Medarex and Centocor, see WO 02/12502
  • adalimumab Human anti-TNF mAb, described in US 6,090,382 as D2E7.
  • Additional TNF antibodies which may be used in the invention are described in U.S. Patent Nos.
  • the TNF ⁇ inhibitor is a TNF fusion protein, e.g., etanercept (Enbrel ® , Amgen; described in WO 91/03553 and WO 09/406476, incorporated by reference herein) or p55TNFRlgG (Lenercept).
  • the TNF ⁇ inhibitor is a recombinant TNF binding protein (r-TBP-I) (Serono).
  • antibody is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHl, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4.
  • the antibodies of the invention are described in further detail in U.S. Patent Nos. 6,090,382; 6,258,562; and 6,509,015, and in U.S. Patent Application Serial Nos. 09/801185 and 10/302356, each of which is incorporated herein by reference in its entirety.
  • antibody portion refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen ⁇ e.g., hTNF ⁇ ). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHl domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHl domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al, (1989) Nature 341:544-546 ), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CHl domains
  • a F(ab')2 fragment a bivalent fragment comprising two Fab fragments linked by
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. ScL USA 85:5879-5883) .
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
  • Other forms of single chain antibodies, such as diabodies are also encompassed.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. ScL USA 90:6444-6448; Poljak, RJ., et al. (1994) Structure 2:1121-1123).
  • the antibody portions of the invention are described in further detail in U.S. Patent Nos. 6,090,382, 6,258,562, 6,509,015, and in U.S. Patent Application Serial Nos. 09/801185 and 10/302356, each of which is incorporated herein by reference in its entirety.
  • Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins. Binding fragments include Fab, Fab', F(ab') 2 , Fabc, Fv, single chains, and single-chain antibodies. Other than “bispecific” or “bifunctional” immunoglobulins or antibodies, an immunoglobulin or antibody is understood to have each of its binding sites identical. A “bispecific” or “bifunctional antibody” is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et al, J. Immunol. 148, 1547-1553 (1992).
  • a “conservative amino acid substitution”, as used herein, is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta- branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • the term "human antibody”, as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the human TNF antibody is adalimumab (also referred to as Humira and D2E7).
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal W
  • human immunoglobulin genes e.g., a mouse
  • human immunoglobulin genes see e.g., Taylor, L.D. et al. (1992) Nucl. Acids Res. 20:6287
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an "isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTNFcc is substantially free of antibodies that specifically_bind antigens other than hTNF ⁇ ).
  • An isolated antibody that specifically binds hTNF ⁇ may, however, have cross-reactivity to other antigens, such as TNFoc molecules from other species (discussed in further detail below).
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • a “neutralizing antibody”, as used herein is intended to refer to an antibody whose binding to hTNF ⁇ results in inhibition of the biological activity of hTNF ⁇ .
  • This inhibition of the biological activity of hTNF ⁇ can be assessed by measuring one or more indicators of hTNF ⁇ biological activity, such as hTNF ⁇ -induced cytotoxicity (either in vitro or in vivo), hTNF ⁇ -induced cellular activation and hTNF ⁇ binding to hTNF ⁇ receptors.
  • indicators of hTNF ⁇ biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art (see U.S. Patent No. 6,090,382).
  • the ability of an antibody to neutralize hTNF ⁇ activity is assessed by inhibition of hTNF ⁇ -induced cytotoxicity of L929 cells.
  • the ability of an antibody to inhibit hTNF ⁇ -induced expression of ELAM-I on HUVEC, as a measure of hTNF ⁇ -induced cellular activation can be assessed.
  • surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ).
  • BIAcore Biosensor AB
  • J ⁇ nsson et al. (1993) Ann. Biol. CHn. 51:19; Jonsson et al. (1991) Biotechniques 11:620-627; Johnsson et al. (1995) /. MoI Recognit. 8:125; and Johnnson et al. (1991) Anal. Biochem.l9S:26S.
  • K o ff is intended to refer to the off rate constant for dissociation of an antibody from the antibody/antigen complex.
  • Kj is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
  • ICs 0 is intended to refer to the concentration of the inhibitor required to inhibit the biological endpoint of interest, e.g., neutralize cytotoxicity activity.
  • nucleic acid molecule is intended to include DNA molecules and RNA molecules.
  • a nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
  • isolated nucleic acid molecule as used herein in reference to nucleic acids encoding antibodies or antibody portions (e.g., VH, VL, CDR3) that bind hTNF ⁇ , is intended to refer to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than hTNF ⁇ , which other sequences may naturally flank the nucleic acid in human genomic DNA.
  • an isolated nucleic acid of the invention encoding a VH region of an anti- hTNF ⁇ antibody contains no other sequences encoding other VH regions that bind antigens other than hTNF ⁇ .
  • vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated.
  • Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome.
  • vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • Other vectors e.g., non-episomal mammalian vectors
  • certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors").
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
  • viral vectors e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses
  • the term "recombinant host cell” or simply “host cell”
  • host cell is intended to refer to a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell” as used herein.
  • dose refers to an amount of TNF ⁇ inhibitor, e.g., a TNF ⁇ antibody, which is administered to a subject.
  • multiple- variable dose includes different doses of a TNF ⁇ inhibitor which are administered to a subject for therapeutic treatment.
  • Multiple- variable dose regimen or “multiple-variable dose therapy” describe a treatment schedule which is based on administering different amounts of a human TNF ⁇ antibody, or antigen-binding portion thereof, at various time points throughout the course of treatment.
  • the invention describes a multiple- variable dose method of treatment comprising an induction phase and a treatment phase, wherein a human TNF ⁇ antibody, or antigen-binding portion thereof, is administered at a higher dose during the induction phase than the treatment phase.
  • Multiple-variable dose regimens using the human TNF ⁇ antibody of the invention are described in U.S. Appln. No. 11/104117.
  • the term "induction phase” or "loading phase” refers to a period of treatment comprising administration of a TNF ⁇ inhibitor to a subject in order to attain a threshold level.
  • at least one induction dose of TNF ⁇ inhibitor is administered to a subject suffering from a disorder in which TNF ⁇ is detrimental.
  • threshold level refers to a therapeutically effective level of a TNF ⁇ inhibitor in a subject.
  • a threshold level is achieved by administering at least one induction dose during the induction phase of treatment. Any number of induction doses may be administered to achieve a threshold level of a human TNF ⁇ antibody, or antigen-binding portion thereof. Once a threshold level is achieved, the treatment phase is initiated.
  • induction dose or “loading dose,” used interchangeably herein, refers to the first dose of a human TNF ⁇ antibody, or antigen-binding portion thereof, which is larger in comparison to the maintenance or treatment dose.
  • the induction dose can be a single dose or, alternatively, a set of doses.
  • the induction dose is often used to bring the drug in the body to a steady state amount, and may be used to which to achieve maintenance drug levels quickly.
  • An induction dose is subsequently followed by administration of smaller doses of a human TNF ⁇ antibody, or antigen-binding portion thereof, i.e., the treatment dose.
  • the induction dose is administered during the induction phase of therapy.
  • the induction dose is at least twice the given amount of the treatment dose.
  • the induction dose of D2E7 is about 160 mg. In another embodiment, the induction dose of D2E7 is about 80 mg.
  • treatment phase refers to a period of treatment comprising administration of a human TNF ⁇ antibody, or antigen- binding portion thereof, to a subject in order to maintain a desired therapeutic effect.
  • the treatment phase follows the induction phase, and, therefore, is initiated once a threshold level is achieved.
  • treatment dose or “maintenance dose” is the amount of a human
  • a treatment dose is administered subsequent to the induction dose.
  • a treatment dose can be a single dose or, alternatively, a set of doses.
  • a treatment dose is administered during the treatment phase of therapy. Treatment doses are smaller than the induction dose and can be equal to each other when administered in succession.
  • the invention describes at least one induction dose of D2E7 of about 160 mg, followed by at least one treatment dose of about 80 mg.
  • the invention describes at least one induction dose of D2E7 of 80 mg, followed by at least one treatment dose of 40 mg.
  • the treatment dose is administered at least two weeks following the induction dose.
  • a “dosage regimen” or “dosing regimen” includes a treatment regimen based on a determined set of doses.
  • the TNF ⁇ antibody is administered for the treatment of depression using dosing regimen selected from the group consisting of a biweekly dosing regimen, a multiple variable dose regimen, and a weekly dosing regimen
  • the invention describes a multiple variable dosage regimen for the treatment of depression, wherein a TNF ⁇ antibody, such as adalimumab/D2E7, is first administered as an induction dose and then administered in treatment doses which are lower than that of the induction dose.
  • dosing refers to the administration of a substance
  • a human TNF ⁇ antibody e.g., a human TNF ⁇ antibody, or antigen-binding portion thereof
  • a therapeutic objective e.g., the treatment of a TNF ⁇ -associated disorder
  • biweekly dosing regimen refers to the time course of administering a substance (e.g., an anti-TNF ⁇ antibody) to a subject to achieve a therapeutic objective (e.g., the treatment of a TNF ⁇ -associated disorder).
  • the biweekly dosing regimen is not intended to include a weekly dosing regimen.
  • the substance is administered every 9-19 days, more preferably, every 11-17 days, even more preferably, every 13-15 days, and most preferably, every 14 days.
  • Biweekly dosing regimens which may be used in accordance with the invention are described in US application no. 10/163657, incorporated by reference herein.
  • a first agent in combination with a second agent includes co-administration of a first agent and a second agent, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent.
  • the present invention includes methods of combination therapeutic treatment and combination pharmaceutical compositions.
  • the invention provides a combination therapy for treating depression or symptoms related thereto comprising administering a human TNF ⁇ antibody, or antigen-binding portion thereof, and an anti-depressant agent.
  • the combination therapy of the invention comprises administration of D2E7 and an antidepressant.
  • concomitant as in the phrase “concomitant therapeutic treatment” includes administering an agent in the presence of a second agent.
  • a concomitant therapeutic treatment method includes methods in which the first, second, third, or additional agents are co-administered.
  • a concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, wherein the second or additional agents, for example, may have been previously administered.
  • a concomitant therapeutic treatment method may be executed step- wise by different actors.
  • one actor may administer to a subject a first agent and a second actor may administer to the subject a second agent, and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first agent (and additional agents) are after administration in the presence of the second agent (and additional agents).
  • the actor and the subject may be the same entity ⁇ e.g., human).
  • combination therapy refers to the administration of two or more therapeutic substances, e.g., an anti-TNF ⁇ antibody and another drug.
  • the other drug(s) may be administered concomitant with, prior to, or following the administration of a human TNF ⁇ antibody, or antigen-binding portion thereof.
  • depression refers to a clinical syndrome that includes a persistent sad mood or loss of interest in activities.
  • the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria can be used to diagnose patients as suffering from depression (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders-Text Revision. 4th ed. Washington: American Psychiatric Association; 2000).
  • DSC-10 International Classification of Disease, version 10 (IDC-10), of the World Health Organization, lists criteria for depression. Examples of types of depression or depressive disorders include, but are not limited to, dysthmic disorder, bipolar disorder, major depression, and cyclothymic disorder.
  • TNF ⁇ - mediated depression or “TNF ⁇ -related depression” refers to depression which is associated with increased TNF ⁇ activity or levels.
  • TNF ⁇ -mediated depression is identified in a subject who has an increase in TNF ⁇ serum levels relative to levels normally seen in non-depressed subjects.
  • a subject having a disorder associated with detrimental TNF ⁇ activity such as, but not limited to, rheumatoid arthritis, Crohn's disease, and psoriasis, may also have TNF ⁇ -mediated depression.
  • the method of the invention is used to treat depression.
  • the method of the invention is used to treat depression in a subject having an additional disorder in which TNF ⁇ activity is detrimental.
  • systemic administration refers to a method of administering a TNF ⁇ inhibitor, such as a TNF ⁇ antibody, or antigen-binding fragment thereof, to a subject via the blood stream.
  • Systemic administration provides inhibition of peripheral TNF ⁇ in contrast to direct administration to the central nervous system which provides for inhibition of central TNF ⁇ .
  • systemic administration excludes perispinal administration of the TNF ⁇ inhibitor, e.g., a TNF ⁇ antibody, for methods of treatment of depression.
  • An example of systemic administration includes subcutaneous administration, as well as intraperitoneal (ip) administration and intravenous administration.
  • kit refers to a packaged product comprising components with which to administer a TNF ⁇ inhibitor, such as a TNF ⁇ antibody for treatment of a TNF ⁇ -mediated depression.
  • the kit preferably comprises a box or container that holds the components of the kit.
  • the box or container is affixed with a label or a Food and Drug Administration approved protocol for treating depression.
  • the box or container holds components of the invention which are preferably contained within plastic, polyethylene, polypropylene, ethylene, or propylene vessels.
  • the vessels can be capped-tubes or bottles.
  • the kit can also include instructions for administering the TNF ⁇ antibody of the invention.
  • the kit of the invention includes the formulation comprising the human antibody D2E7, as described in PCT/IB03/04502 and U.S. Appln. No. 10/222140.
  • TNF ⁇ Inhibitors of the Invention provides a method of treating depression through systemic administration of a TNF ⁇ inhibitor a human TNF ⁇ antibody, or antigen-binding portion thereof.
  • these methods include administration of isolated human antibodies, or antigen-binding portions thereof, that bind to human TNF ⁇ with high affinity and a low off rate, and have a high neutralizing capacity.
  • the human antibodies of the invention are recombinant, neutralizing human anti-hTNF ⁇ antibodies.
  • D2E7 The most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7, also referred to as HUMDR.A ® and adalimumab
  • D2E7 VL region is shown in SEQ ID NO: 1
  • amino acid sequence of the D2E7 VH region is shown in SEQ ID NO: 2.
  • HUMIRA ® have been described in Salfeld et al, U.S. Patent Nos. 6,090,382, 6,258,562, and 6,509,015, which are each incorporated by reference herein.
  • the methods of the invention may also be performed using chimeric and humanized murine anti-hTNF ⁇ antibodies which have undergone clinical testing for treatment of rheumatoid arthritis (see e.g., Elliott, MJ., et al. (1994) Lancet 344:1125-1127; Elliot, M.J., et al (1994) Lancet 344:1105-1110; Rankin, E.G., et al. (1995) Br. J. Rheumatol. 34:334-342).
  • the method of treating depression of the invention includes the systemic administration of D2E7 antibodies and antibody portions, D2E7-related antibodies and antibody portions, and other human antibodies and antibody portions with equivalent properties to D2E7, such as high affinity binding to hTNF ⁇ with low dissociation kinetics and high neutralizing capacity.
  • the invention provides treatment with an isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNF ⁇ with a K ⁇ of 1 x 10 ⁇ 8 M or less and a K o ff rate constant of 1 x 10 ⁇ 3 s"l or less, both determined by surface plasmon resonance, and neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10 ⁇ 7 M or less.
  • the isolated human antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K o ff of 5 x 10 " 4 s ⁇ l or less, or even more preferably, with a K o ff of 1 x 10 ⁇ 4 s"l or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNF ⁇ cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10" ⁇ M or less, even more preferably with an IC50 of 1 x 10 ⁇ 9 M or less and still more preferably with an IC50 of 1 x 10" ⁇ M or less.
  • the antibody is an isolated human recombinant antibody, or an antigen-binding portion thereof.
  • antibody heavy and light chain CDR3 domains play an important role in the binding specificity/affinity of an antibody for an antigen.
  • the invention pertains to methods of treating depression by administering human antibodies that have slow dissociation kinetics for association with hTNF ⁇ and that have light and heavy chain CDR3 domains that structurally are identical to or related to those of D2E7.
  • Position 9 of the D2E7 VL CDR3 can be occupied by Ala or Thr without substantially affecting the K o ff.
  • a consensus motif for the D2E7 VL CDR3 comprises the amino acid sequence: Q-R- Y-N- R-A-P-Y-(TYA) (SEQ ID NO: 3).
  • position 12 of the D2E7 VH CDR3 can be occupied by Tyr or Asn, without substantially affecting the K o ff.
  • a consensus motif for the D2E7 VH CDR3 comprises the amino acid sequence: V-S-Y-L- S-T-A-S-S-L-D-(Y/N) (SEQ ID NO: 4).
  • the CDR3 domain of the D2E7 heavy and light chains is amenable to substitution with a single alanine residue (at position 1, 4, 5, 7 or 8 within the VL CDR3 or at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 within the VH CDR3) without substantially affecting the K o ff .
  • substitutions by alanine substitution of other amino acids within the CDR3 domains may be possible while still retaining the low off rate constant of the antibody, in particular substitutions with conservative amino acids.
  • no more than one to five conservative amino acid substitutions are made within the D2E7 VL and/or VH CDR3 domains.
  • no more than one to three conservative amino acid substitutions are made within the D2E7 VL and/or VH CDR3 domains.
  • conservative amino acid substitutions should not be made at amino acid positions critical for binding to hTNF ⁇ .
  • Positions 2 and 5 of the D2E7 VL CDR3 and positions 1 and 7 of the D2E7 VH CDR3 appear to be critical for interaction with hTNF ⁇ and thus, conservative amino acid substitutions preferably are not made at these positions (although an alanine substitution at position 5 of the D2E7 VL CDR3 is acceptable, as described above) (see U.S. Patent No. 6,090,382).
  • the invention provides methods of treating depression by systemic administration of an isolated human antibody, or antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains the following characteristics: a) dissociates from human TNF ⁇ with a K o ff rate constant of 1 x 10 ⁇ 3 s ⁇ l or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
  • the antibody, or antigen-binding portion thereof dissociates from human TNF ⁇ with a K o ff of 5 x 10 ⁇ 4 s ⁇ l or less. Even more preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNF ⁇ with a K o ff of 1 x 10 ⁇ 4 s"l or less.
  • the invention provides methods of treating depression by systemic administration of an isolated human antibody, or antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ K) NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the LCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 (i.e., the D2E7 VL CDR2) and the HCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6 (i.e., the D2E7 VH CDR2).
  • the LCVR further has CDRl domain comprising the amino acid sequence of SEQ ID NO: 7 (i.e., the D2E7 VL CDRl) and the HCVR has a CDRl domain comprising the amino acid sequence of SEQ ID NO: 8 (i.e., the D2E7 VH CDRl).
  • the framework regions for VL preferably are from the V K I human germline family, more preferably from the A20 human germline Vk gene and most preferably from the D2E7 VL framework sequences shown in Figures IA and IB of U.S. Patent No. 6,090,382.
  • the framework regions for VH preferably are from the VJJ3 human germline family, more preferably from the DP-31 human germline VH gene and most preferably from the D2E7 VH framework sequences shown in Figures 2A and 2B of U.S. Patent No. 6,090,382.
  • the invention provides methods of treating depression by the administration of an isolated human antibody, or antigen-binding portion thereof.
  • the antibody or antigen-binding portion thereof preferably contains a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 (i.e., the D2E7 VL) and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 (i.e., the D2E7 VH).
  • the antibody comprises a heavy chain constant region, such as an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region.
  • the heavy chain constant region is an IgGl heavy chain constant region or an IgG4 heavy chain constant region.
  • the antibody can comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region.
  • the antibody comprises a kappa light chain constant region.
  • the antibody portion can be, for example, a Fab fragment or a single chain Fv fragment.
  • the invention methods of treating depression comprises administration of an isolated human antibody, or an antigen-binding portions thereof, containing D2E7 -related VL and VH CDR3 domains.
  • a light chain variable region having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26 or with a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, S
  • the method of the invention includes treating depression by systemically administering a TNF ⁇ inhibitor, including, but not limited to, an anti- TNF ⁇ antibody, or a fragment thereof, including infliximab (Remicade ® , Johnson and Johnson; described in U.S. Patent No.
  • a TNF ⁇ inhibitor including, but not limited to, an anti- TNF ⁇ antibody, or a fragment thereof, including infliximab (Remicade ® , Johnson and Johnson; described in U.S. Patent No.
  • CDP571 a humanized monoclonal anti-TNF-alpha IgG4 antibody
  • CDP 870 a humanized monoclonal anti-TNF-alpha antibody fragment
  • an anti-TNF dAb Peptech
  • CNTO 148 golimumab; Medarex and Centocor, see WO 02/12502
  • adalimumab Human anti-TNF mAb, described in US 6,090,382 as D2E7.
  • the TNF ⁇ inhibitor is a recombinant TNF binding protein (r-TBP-I) (Serono).
  • the TNF ⁇ antibody used in the methods and compositions of the invention may be modified for improved treatment of depression.
  • the TNF ⁇ antibody or antigen binding fragments thereof is chemically modified to provide a desired effect.
  • pegylation of antibodies and antibody fragments of the invention may be carried out by any of the pegylation reactions known in the art, as described, for example, in the following references: Focus on Growth Factors 3:4-10 (1992); EP 0 154316; and EP 0401 384 (each of which is incorporated by reference herein in its entirety).
  • the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive polyethylene glycol molecule (or an analogous reactive water-soluble polymer).
  • a preferred water-soluble polymer for pegylation of the antibodies and antibody fragments of the invention is polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • polyethylene glycol is meant to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (Cl-ClO) alkoxy- or aryloxy- polyethylene glycol.
  • Methods for preparing pegylated antibodies and antibody fragments of the invention will generally comprise the steps of (a) reacting the antibody or antibody fragment with polyethylene glycol, such as a reactive ester or aldehyde derivative of PEG, under conditions whereby the antibody or antibody fragment becomes attached to one or more PEG groups, and (b) obtaining the reaction products. It will be apparent to one of ordinary skill in the art to select the optimal reaction conditions or the acylation reactions based on known parameters and the desired result.
  • Pegylated antibodies and antibody fragments may generally be used to treat TNF ⁇ -related disorders of the invention by systemic administration of the TNF ⁇ antibodies and antibody fragments described herein. Generally the pegylated antibodies and antibody fragments have increased half-life, as compared to the nonpegylated antibodies and antibody fragments. The pegylated antibodies and antibody fragments may be employed alone, together, or in combination with other pharmaceutical compositions.
  • TNF ⁇ antibodies or fragments thereof can be altered wherein the constant region of the antibody is modified to reduce at least one constant region-mediated biological effector function relative to an unmodified antibody.
  • the immunoglobulin constant region segment of the antibody can be mutated at particular regions necessary for Fc receptor (FcR) interactions (see e.g., Canfield, S.M. and S.L. Morrison (1991) /. Exp. Med. 173: 1483-1491 ; and Lund, J. et al. (1991) /. of Immunol. 147:2657-2662).
  • Reduction in FcR binding ability of the antibody may also reduce other effector functions which rely on FcR interactions, such as opsonization and phagocytosis and antigen-dependent cellular cytotoxicity.
  • An antibody or antibody portion used in the methods of the invention can be derivatized or linked to another functional molecule (e.g., another peptide or protein).
  • an antibody or antibody portion of the invention is intended to include derivatized and otherwise modified forms of the human anti-hTNF ⁇ antibodies described herein, including immunoadhesion molecules.
  • an antibody or antibody portion of the invention can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
  • another antibody e.g., a bispecific antibody or a diabody
  • a detectable agent e.g., a cytotoxic agent, a pharmaceutical agent
  • a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a
  • One type of derivatized antibody is produced by crosslinking two or more antibodies (of the same type or of different types, e.g., to create bispecific antibodies).
  • Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N- hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate).
  • Such linkers are available from Pierce Chemical Company, Rockford, IL.
  • Useful detectable agents with which an antibody or antibody portion of the invention may be derivatized include fluorescent compounds.
  • Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5- dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin and the like.
  • An antibody may also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product.
  • the detectable agent horseradish peroxidase when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is detectable.
  • An antibody may also be derivatized with biotin, and detected through indirect measurement of avidin or streptavidin binding.
  • An antibody, or antibody portion, used in the methods or compositions of the invention can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell.
  • a host cell is transfected with one or more recombinant expression vectors carrying DNA fragments encoding the immunoglobulin light and heavy chains of the antibody such that the light and heavy chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the antibodies can be recovered.
  • Standard recombinant DNA methodologies are used to obtain antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, such as those described in Sambrook, Fritsch and Maniatis (eds), Molecular Cloning; A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989), Ausubel, F.M. et al. (eds.) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989) and in U.S. Patent No. 4,816,397 by Boss et al.
  • DNA fragments encoding the light and heavy chain variable regions are first obtained. These DNAs can be obtained by amplification and modification of germline light and heavy chain variable sequences using the polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • Germline DNA sequences for human heavy and light chain variable region genes are known in the art (see e.g., the "Vbase” human germline sequence database; see also Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I.M., et al.
  • a member of the VJJ3 family of human germline VH genes is amplified by standard PCR.
  • the DP-31 VH germline sequence is amplified.
  • a member of the V K I family of human germline VL genes is amplified by standard PCR.
  • the A20 VL germline sequence is amplified.
  • these sequences can be mutated to encode the D2E7 or D2E7-related amino acid sequences disclosed herein.
  • the amino acid sequences encoded by the germline VH and VL DNA sequences are first compared to the D2E7 or D2E7-related VH and VL amino acid sequences to identify amino acid residues in the D2E7 or D2E7-related sequence that differ from germline. Then, the appropriate nucleotides of the germline DNA sequences are mutated such that the mutated germline sequence encodes the D2E7 or D2E7-related amino acid sequence, using the genetic code to determine which nucleotide changes should be made.
  • Mutagenesis of the germline sequences is carried out by standard methods, such as PCR- mediated mutagenesis (in which the mutated nucleotides are incorporated into the PCR primers such that the PCR product contains the mutations) or site-directed mutagenesis.
  • PCR- mediated mutagenesis in which the mutated nucleotides are incorporated into the PCR primers such that the PCR product contains the mutations
  • site-directed mutagenesis Once DNA fragments encoding D2E7 or D2E7-related VH and VL segments are obtained (by amplification and mutagenesis of germline VH and VL genes, as described above), these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene.
  • VL- or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
  • operatively linked is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • the isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CHl, CH2 and CH3).
  • heavy chain constant regions CHl, CH2 and CH3
  • the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgGl or IgG4 constant region.
  • the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CHl constant region.
  • the isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
  • the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. ScL USA 85:5879-5883; McCafferty et al, Nature (1990) 348:552-554).
  • a flexible linker e.g., encoding the amino acid sequence (Gly4-Ser)3
  • DNAs encoding partial or full-length light and heavy chains, obtained as described above, are inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
  • operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
  • the antibody genes are inserted into the expression vector by standard methods ⁇ e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
  • the expression vector Prior to insertion of the D2E7 or D2E7 -related light or heavy chain sequences, the expression vector may already carry antibody constant region sequences.
  • one approach to converting the D2E7 or D2E7-related VH and VL sequences to full-length antibody genes is to insert them into expression vectors already encoding heavy chain constant and light chain constant regions, respectively, such that the VH segment is operatively linked to the CH segment(s) within the vector and the VL segment is operatively linked to the CL segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
  • the term "regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Patents Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et ah).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
  • Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
  • the various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE- dextran transfection and the like.
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in RJ. Kaufman and P.A. Sharp (1982) MoI. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
  • Chinese Hamster Ovary CHO cells
  • dhfr- CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in RJ. Kaufman and P.A. Sharp (1982) MoI. Biol. 159:601-621
  • NSO myeloma cells
  • the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. It is understood that variations on the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of this invention. Recombinant DNA technology may also be used to remove some or all of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to hTNFcc. The molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention.
  • bifunctional antibodies may be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than hTNF ⁇ by crosslinking an antibody of the invention to a second antibody by standard chemical crosslinking methods.
  • a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection.
  • the antibody heavy and light chain genes are each operatively linked to CMV enhancer/ AdMLP promoter regulatory elements to drive high levels of transcription of the genes.
  • the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification. The selected transformant host cells are culture to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium.
  • Recombinant human antibodies of the invention in addition to D2E7 or an antigen binding portion thereof, or D2E7-related antibodies disclosed herein can be isolated by screening of a recombinant combinatorial antibody library, preferably a scFv phage display library, prepared using human VL and VH cDNAs prepared from mRNA derived from human lymphocytes. Methodologies for preparing and screening such libraries are known in the art. In addition to commercially available kits for generating phage display libraries (e.g., the Pharmacia Recombinant Phage Antibody System, catalog no.
  • a murine anti-hTNF ⁇ antibody having high affinity and a low off rate constant for hTNF ⁇ is first used to select human heavy and light chain sequences having similar binding activity toward hTNF ⁇ , using the epitope imprinting methods described in Hoogenboom et al, PCT Publication No. WO 93/06213.
  • the antibody libraries used in this method are preferably scFv libraries prepared and screened as described in McCafferty et al, PCT Publication No.
  • the scFv antibody libraries preferably are screened using recombinant human TNF ⁇ as the antigen. Once initial human VL and VH segments are selected, "mix and match" experiments, in which different pairs of the initially selected VL and VH segments are screened for hTNF ⁇ binding, are performed to select preferred VL/VH pair combinations.
  • the VL and VH segments of the preferred VL/VH pair(s) can be randomly mutated, preferably within the CDR3 region of VH and/or VL, in a process analogous to the in vivo somatic mutation process responsible for affinity maturation of antibodies during a natural immune response.
  • This in vitro affinity maturation can be accomplished by amplifying VH and VL regions using PCR primers complimentary to the VH CDR3 or VL CDR3, respectively, which primers have been "spiked” with a random mixture of the four nucleotide bases at certain positions such that the resultant PCR products encode VH and VL segments into which random mutations have been introduced into the VH and/or VL CDR3 regions.
  • These randomly mutated VH and VL segments can be rescreened for binding to hTNF ⁇ and sequences that exhibit high affinity and a low off rate for hTNF ⁇ binding can be selected.
  • nucleic acid encoding the selected antibody can be recovered from the display package (e.g. , from the phage genome) and subcloned into other expression vectors by standard recombinant DNA techniques. If desired, the nucleic acid can be further manipulated to create other antibody forms of the invention (e.g., linked to nucleic acid encoding additional immunoglobulin domains, such as additional constant regions).
  • the DNA encoding the antibody is cloned into a recombinant expression vector and introduced into a mammalian host cells, as described in further detail in above.
  • the invention provides methods of treating depression comprising inhibiting, peripheral TNF ⁇ .
  • the invention also provides methods for treating depression in a subject suffering from or at risk of suffering from depression, which may be associated with TNF ⁇ , comprising systemically administering a TNF ⁇ antibody.
  • the TNF ⁇ antibody is administered in combination with an additional therapeutic agent, such as an antidepressant agent.
  • the TNF ⁇ antibody is D2E7, also referred to as HUMIR A ® (adalimumab). TNF ⁇ has been shown to be associated with depression.
  • TNF ⁇ -mediated depression is intended to include depressive disorders in which the presence of TNF ⁇ in a subject suffering from the depression has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder.
  • TNF ⁇ -mediated depression is a depression in which inhibition of TNF ⁇ activity is expected to alleviate the symptoms and/or progression of the depression, e.g., improve the overall mood of the affected individual, improve self-esteem of the subject.
  • Such disorders may be evidenced, for example, by an increase in the concentration of
  • TNF ⁇ in a biological fluid of a subject suffering from the disorder e.g., an increase in the concentration of TNF ⁇ in serum, plasma, synovial fluid, etc. of the subject
  • an anti-TNF ⁇ antibody as described above.
  • depression contemplates all diseases and conditions which are associated with depression including those classified in the IDC-10 and DSM-IV rating scales. Symptoms of depression include, but are not limited to, feeling sad, hopeless, worthless, or pessimistic.
  • the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria can be used to diagnose patients as suffering from depression (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders-Text Revision. 4th ed. Washington: American Psychiatric Association; 2000), incorporated by reference herein.
  • the International Classification of Disease, version 10 (incorporated by reference herein), of the World Health
  • depression or depressive disorders which may be treated by the methods of the invention include, but are not limited to, major depression, dysthymic disorder, cyclothymic disorder, bipolar disorder, and depressive episodes associated with other mood disorders, including seasonal mood disorders such as seasonal affective disorder, subsyndromal depression, single episode depression, post-partum depression, and mood disorders due to a general medical condition, substance induced mood disorder, recurrent or treatment-resistant depression, child abuse induced depression, atypical depression, cyclothymia, menstrual-related dysphoria, depression associated with somatoform disorder, and treatment-resistant depression.
  • seasonal mood disorders such as seasonal affective disorder, subsyndromal depression, single episode depression, post-partum depression, and mood disorders due to a general medical condition, substance induced mood disorder, recurrent or treatment-resistant depression, child abuse induced depression, atypical depression, cyclothymia, menstrual-related dysphoria, depression associated with somatoform disorder, and treatment-resistant depression.
  • the invention provides methods of treating major depression comprising the systemic administration of a TNF ⁇ antibody, including a human TNF ⁇ antibody, or antigen-binding fragment thereof.
  • Major depression is also commonly referred to as unipolar depression and major depressive disorder.
  • Major depression is characterized as a subject having five or more symptoms of depression for a specific time period, typically at least 2 weeks.
  • people with major depression often have behavior changes, such as new eating and sleeping patterns, and may have thoughts of suicide.
  • Various forms of major depression including a single episode or recurrent major depression, may be treated using a human TNF ⁇ antibody, or antigen-binding fragment thereof.
  • Refractory (or treatment resistant) major depression may also be treated with the methods of the invention.
  • Treatment-resistant depression is a common clinical occurrence among patients treated for major depressive disorder. Methods of identifying TRD are described in Souery et al. (2006) J Clin Psychiatry 67: 16-22, incorporated by reference herein.
  • the invention provides a method of treating a dysthmic disorder comprising systemically administering a human TNF ⁇ antibody, or antigen- binding fragment thereof.
  • Dysthmic disorder, or dysthmia is also commonly referred to as neurotic depression or chronic depression. Symptoms of dysthmia include, but are not limited to, poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, and feelings of hopelessness. Symptoms of dysthmia are often not as severe in affected subjects as in other forms of depression.
  • Major depressive disorder and dysthymic disorder are differentiated based on chronicity, severity and persistence.
  • major depression the depressed mood is usually present for about two weeks.
  • dysthymic disorder the depressed mood is usually present most days over a period of about two years.
  • major depressive disorder is characterized by its sharp contrast to usual functioning.
  • a person with a major depressive episode can be functioning and feeling normally and suddenly develops severe symptoms of depression.
  • a person with dysthymic disorder has chronic depression with less severe symptoms than major depression for generally a longer time span.
  • Cyclothymic Disorder The invention also provides methods of treating a cyclothymic disorder comprising systemically administering a TNF ⁇ antibody, including, for example, a human TNF ⁇ antibody, or antigen-binding fragment thereof.
  • Cyclothymic disorder also called cyclothymia, is a mild form of bipolar disorder, characterized by alternating episodes of mood swings from mild or moderate depression to hypomania. Hypomania is defined as periods of elevated mood, euphoria, and excitement that do not cause the person to become disconnected from reality.
  • a TNF ⁇ antibody such as a human TNF ⁇ antibody, or antigen-binding fragment thereof, may also be used to treat a subject having bipolar disorder, also referred to as manic depression and bipolar affective disorder.
  • Bipolar disorder is characterized by periods of excitability (mania) alternating with periods of depression. The "mood swings" between mania and depression can be very abrupt and may be intermittent.
  • Bipolar disorders can be categorized as either bipolar I disorder or bipolar II disorder.
  • Bipolar I disorder is characterized by one or more manic episodes or mixed episodes and often one or more major depressive episodes. A depressive episode may last for several weeks or months, alternating with intense symptoms of mania that may last just as long. Between episodes, there may be periods of normal functioning.
  • Bipolar II disorder is characterized by one or more major depressive episodes accompanied by at least one hypomanic episode. Hypomanic episodes have symptoms similar to manic episodes, but are less severe. Between episodes, an affected subject may have periods of normal functioning. Symptoms of bipolar II disorder may also be related to seasonal changes. Issues and treatments involving bipolar depression are described in Thase (2005) Harv Rev Psychiatry. 2005 Sep-Oct;13(5):257-71.
  • depressive disorders referred to above may be associated with additional features, including catatonic features, melancholic features, atypical features, and postpartum onset of the disorder.
  • TNF ⁇ antibodies may also be used to treat refractory or treatment resistant depression.
  • Refractory depression may occur in patients who have been treated for depression, but have failed to respond to therapy.
  • Treatment of depression may also be determined using measures of serum levels of TNFoc and/or depression symptoms (e.g. HAM-D) in depressed patients before and after completion of the treatment with Humira (adalimumab).
  • Depression may be diagnosed by one of ordinary skill in the art through the use of an accepted index or scale which determines the depression status of an individual.
  • any of the following indices / scales, as well as others known in the art may be used to determine the efficacy of a TNF ⁇ inhibitor, e.g., a TNF ⁇ antibody, for treating depression in a subject in accordance with the invention.
  • An improvement in the index or scale known in the art, such as those described below, indicates that the TNF ⁇ inhibitor is effective for the treatment of depression. Such improvements may be determined by comparing the pre- treatment and post-treatment score of the subject having depression.
  • HAM-D Hamilton depression rating scale
  • the 24-item HAM-D questionnaire is used to rate the severity of a patient's depression and evaluate the efficacy of antidepressant therapy.
  • HAM-D scores are generally interpreted as follows: very severe, >23; severe, 19-22; moderate, 14-18; mild, 8-13; and no depression, 0-7.
  • Response to treatment can be defined as patients with a 50% or more decrease in HAM-D score.
  • Remission is defined as a HAM-D score of 7 or less.
  • a TNF ⁇ inhibitor e.g., a TNF ⁇ antibody
  • a TNF ⁇ inhibitor is administered systemically for the treatment of depression, wherein treatment of depression is determined by an improvement in the HAM-D score of the subject, e.g., a HAM-D score of ⁇ 7 following treatment.
  • HAM-A Hamilton anxiety scale
  • the HAM-A scale consists of 14 items, each defined by series of symptoms, scored on a scale of 0 (not present) to 4.
  • HAM-A scores are generally interpreted as follows: mild, ⁇ 17; mild to moderate, 18-24; and moderate to severe, 25- 30.
  • CGI Clinical Global Impression
  • the CGI scale refers to the global severity of illness and change in the clinical condition over time.
  • the CGI scale consists of three global subscales: severity of illness, global improvement and efficacy index.
  • PKI Patient Global Impression of Improvement
  • indices used to determine the depression status of an individual include the Bech-Rafaelsen Melancholic Scale (MES) (Acta Psychiatrica Scandinavica 106:252-64, 2002), the Montgomery-Asberg depression rating scale (MADRS) (British Journal of Psychiatry 134:382-389, 1979), the major depression index (MDI) (Journal of Affective Disorders 66:159-164, 2001), the Beck depression index (BDI) (Archives of General Psychiatry 4:561-571, 1961), and the hospital anxiety depression scale (HAD) (Acta Psychiatrica Scandinavica 67:361-370, 1983).
  • MES Bech-Rafaelsen Melancholic Scale
  • MADRS Montgomery-Asberg depression rating scale
  • HSD hospital anxiety depression scale
  • Quality of life questionnaires may also used to determine efficacy.
  • quality of life questionnaires measure social functioning. Examples of quality of life questionnaires include: the Social and Occupational Functioning Scale (SOFAS), the Sheehan Disability Scale, the Social Adjustment Scale - Self Report (SAS-SR), the
  • SASS Social Adaptation Self-Evaluation Scale
  • SF-36 Short-Form Health Survey
  • PGWB Psychological General Well-Being Scale
  • WHO-5 WHO-Five Weil-Being Index
  • the methods of the invention may also be used to treat depression which is associated with another disorder, especially a disorder in which TNF ⁇ activity is detrimental.
  • Other types of disorders in which TNF ⁇ activity is detrimental in which the affected subject may also suffer from depression include, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, and psoriatic arthritis.
  • Other examples of disorders which may be associated with depression include coronary heart disease, a neurodegenerative disease, such as a stroke, an infectious disease, and an autoimmune disorder.
  • Examples of autoimmune disorders which may be treated using the method of the invention include psoriasis, psoriatic arthritis, and rheumatoid arthritis.
  • intestinal disorders which may be treated using the method of the invention include inflammatory bowel disease and Crohn's disease. Furthermore, the depressed subject may have Behcet's disease, asthma, and Niemann-Pick disease. TNF- ⁇ -related disorders as described in U.S. Appln. No. 10/622932, WO 2004009776, PCT/US97/02219, and U.S. Pat. No. 6,258,562, each of which is incorporated by reference herein, may also be treated with the methods of the invention.
  • compositions A. Compositions
  • Antibodies and antibody-portions for use in the treatment and preventive methods of the invention can be incorporated into pharmaceutical compositions suitable for systemic administration to a subject with depression.
  • the pharmaceutical composition comprises an antibody, antibody portion, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • compositions for use in the methods of the invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions ⁇ e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
  • the preferred mode of administration is parenteral ⁇ e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody or other TNF ⁇ inhibitor is administered by systemic administration, including intravenous infusion or injection.
  • the antibody, or antigen-binding portion thereof is administered by intramuscular or subcutaneous injection.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the active compound ⁇ i.e., antibody, antibody portion, or other TNF ⁇ inhibitor) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. Supplementary active compounds can also be incorporated into the compositions.
  • an antibody or antibody portion for use in the methods of the invention is coformulated with and/or coadministered with one or more additional therapeutic agents, including an antidepressant agent.
  • an anti-hTNFoc antibody or antibody portion of the invention may be coformulated and/or coadministered with one or more additional antibodies that bind other targets ⁇ e.g., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF ⁇ receptor (see e.g., PCT Publication No.
  • WO 94/06476 and/or one or more chemical agents that inhibit hTNF ⁇ production or activity (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751) or any combination thereof.
  • one or more antibodies of the invention may be used in combination with two or more of the foregoing therapeutic agents.
  • Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible side effects, complications or low level of response by the patient associated with the various monotherapies.
  • the invention includes pharmaceutical compositions comprising an effective amount of a TNF ⁇ inhibitor and a pharmaceutically acceptable carrier, wherein the effective amount of the TNF ⁇ inhibitor may be effective to treat depression.
  • the antibody or antibody portion for use in the methods of the invention is incorporated into a pharmaceutical formulation as described in PCT/IB03/04502 and U.S. Appln. No. 10/222140, incorporated by reference herein.
  • This formulation includes a concentration 50 mg/ml of the antibody D2E7, wherein one pre- filled syringe contains 40 mg of antibody for subcutaneous injection for treatment of depression.
  • the formulation of the invention includes D2E7 and an antidepressant.
  • the antibody D2E7 may also be administered in combination with an antidepressant agent for the treatment of depression.
  • D2E7 and an antidepressant agent are co-administered for treatment of depression.
  • D2E7 and an antidepressant agent are co-formulated for treatment of depression.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • the TNF ⁇ antibodies of the invention can also be administered in the form of protein crystal formulations which include a combination of protein crystals encapsulated within a polymeric carrier to form coated particles.
  • the coated particles of the protein crystal formulation may have a spherical morphology and be microspheres of up to 500 micro meters in diameter or they may have some other morphology and be microparticulates.
  • the enhanced concentration of protein crystals allows the antibody of the invention to be delivered subcutaneously.
  • the TNF ⁇ antibodies of the invention are delivered via a protein delivery system, wherein one or more of a protein crystal formulation or composition, is administered to a subject with a TNF ⁇ -related disorder.
  • compositions and methods of preparing stabilized formulations of whole antibody crystals or antibody fragment crystals are also described in WO 02/072636, which is incorporated by reference herein.
  • a formulation comprising the crystallized antibody fragments described in PCT/JDB 03/04502 and U.S. Appln. No. 10/222140, incorporated by reference herein, are used to treat a TNF ⁇ -related disorder using the multiple- van able dose methods of the invention..
  • the invention provides a method of treating depression comprising inhibiting peripheral TNF ⁇ which is achieved through systemic administration of the antibody to the subject.
  • Antibodies used to treat depression are administered to a subject having depression such that peripheral activity of TNF ⁇ is inhibited.
  • the antibodies and antibody- portions of the present invention can be administered systemically by a variety of methods known in the art, although a preferred route/mode of administration is subcutaneous injection. In another embodiment, administration is via intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and/or mode of systemic administration will vary depending upon the desired results, e.g., type of depression.
  • the TNF ⁇ antibody or antibody portion is administered via subcutaneous administration to the subject.
  • an antibody or antibody portion may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Dosage regimens may be adjusted to provide the optimum desired response ⁇ e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • compositions of the invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of an antibody or antibody portion of the invention.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the antibody, antibody portion, or other TNF ⁇ inhibitor may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody, antibody portion, other TNF ⁇ inhibitor to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody, antibody portion, or other TNF ⁇ inhibitor are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antibody or antibody portion of the invention is 10-180 mg, more preferably 20-160 mg and most preferably about 80 mg.
  • the therapeutically effective amount of an antibody or portion thereof for use in the methods of the invention is 40 mg.
  • the therapeutically effective amount of an antibody or portion thereof for use in the methods of the invention is 80 mg.
  • the therapeutically effective amount of an antibody or portion thereof for use in the methods of the invention is 160 mg. Ranges intermediate to the above recited dosages, e.g. about 78.5 - 81.5, are also intended to be part of this invention.
  • the invention provides a single dose method for treating depression, comprising systemically administering to a subject in need thereof a single dose of a TNF ⁇ human antibody.
  • the anti-TNF ⁇ antibody D2E7.
  • the single dose of anti-TNF ⁇ antibody can be any therapeutically or prophylactically effective amount.
  • a subject is administered either a 20 mg, a 40 mg, or an 80 mg single dose of D2E7.
  • the single dose may be administered through any systemic route, including, for example, subcutaneous administration. Multiple variable dose methods of treatment or prevention can also be used, and are described in U.S. application no. 11/104117, incorporated by reference herein.
  • dosage values may vary with the type and severity of the type of depression to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person systemically administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • kits for administering anti-TNF antibodies for use in the methods of the invention.
  • the kit comprises an antibody and instructions for systemic administration for treatment of depression, e.g., a TNF ⁇ antibody.
  • the instructions may describe how, e.g., subcutaneously, and when, e.g., at week 0 and week 2, the different doses of TNF ⁇ antibody and/or the additional therapeutic agent shall be administered to a subject for treatment.
  • kits containing a pharmaceutical composition comprising an anti-TNF ⁇ antibody and a pharmaceutically acceptable carrier, and one or more pharmaceutical compositions each comprising a drug useful for treating depression and a pharmaceutically acceptable carrier.
  • the kit comprises a single pharmaceutical composition comprising an anti-TNF ⁇ antibody, one or more drugs useful for treating depression and a pharmaceutically acceptable carrier.
  • the kits contain instructions for dosing of the pharmaceutical compositions for the treatment of depression in which the systemic administration of an anti-TNF ⁇ antibody is beneficial.
  • the package or kit alternatively can contain the TNF ⁇ antibody and it can be promoted for use, either within the package or through accompanying information, for the uses or treatment of the disorders described herein.
  • the packaged pharmaceuticals or kits further can include a second agent (as described herein) packaged with or copromoted with instructions for using the second agent with a first agent (as described herein).
  • the invention pertains to pharmaceutical compositions and methods of use thereof for the treatment of depression.
  • the pharmaceutical compositions comprise a first agent that prevents or treats depression.
  • the pharmaceutical composition also may comprise a second agent that is an active pharmaceutical ingredient; that is, the second agent is therapeutic and its function is beyond that of an inactive ingredient, such as a pharmaceutical carrier, preservative, diluent, or buffer.
  • the second agent may be useful in treating or preventing depression.
  • the second agent may diminish or treat at least one symptom(s) associated with the depression.
  • the first and second agents may exert their biological effects by similar or unrelated mechanisms of action; or either one or both of the first and second agents may exert their biological effects by a multiplicity of mechanisms of action.
  • a pharmaceutical composition may also comprise a third compound, or even more yet, wherein the third (and fourth, etc.) compound has the same characteristics of a second agent.
  • the pharmaceutical compositions described herein may have the first and second, third, or additional agents in the same pharmaceutically acceptable carrier or in a different pharmaceutically acceptable carrier for each described embodiment.
  • the first, second, third and additional agent may be administered simultaneously or sequentially within described embodiments.
  • a first and second agent may be administered simultaneously, and a third or additional agent may be administered before or after the first two agents.
  • the combination of agents used within the methods and pharmaceutical compositions described herein may have a therapeutic additive or synergistic effect on the condition(s) or disease(s) targeted for treatment.
  • the combination of agents used within the methods or pharmaceutical compositions described herein also may reduce a detrimental effect associated with at least one of the agents when administered alone or without the other agent(s) of the particular pharmaceutical composition.
  • the toxicity of side effects of one agent may be attenuated by another agent of the composition, thus allowing a higher dosage, improving patient compliance, and improving therapeutic outcome.
  • the additive or synergistic effects, benefits, and advantages of the compositions apply to classes of therapeutic agents, either structural or functional classes, or to individual compounds themselves.
  • an antibody or antibody portion of the invention is coformulated with and/or coadministered with one or more additional therapeutic agents that are useful for treating depression.
  • an anti-hTNF ⁇ antibody, antibody portion may be coformulated and/or coadministered with one or more additional antibodies that bind other targets (e.g., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF ⁇ receptor (see e.g., PCT Publication No.
  • WO 94/064766 and/or one or more chemical agents that inhibit hTNF ⁇ production or activity (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751).
  • one or more antibodies of the invention may be used in combination with two or more of the foregoing therapeutic agents.
  • Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies.
  • the anti-hTNF ⁇ antibody is systemically administered for treatment of depression, the additional therapeutic agent may be administered via a different route.
  • One of ordinary skill in the art would recognize the appropriate means by which the additional agent is administered.
  • the TNF ⁇ antibody of the invention may be used in combination with additional therapeutic agents for the treatment of depression.
  • Additional agents used to treat depression include antidepressant agents.
  • antidepressant agents include, but selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and MAOI's (monoamine oxidase inhibitors).
  • SSRIs include citalopram (Celexa), escitalopram oxalate (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, paxil CR), and sertraline (Zoloft).
  • tricyclic antidepressants examples include imipramine, amitriptyline, clomipramine, doxepin, desipramine, nortriptyline, protriptyline, and trimipramine.
  • MAOIs examples include phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan).
  • Non-limiting examples of other agents that can be used in combination with a TNF ⁇ antibody for the treatment of depression or treatment of depression and an additional disorder include but are not limited to antibodies to or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-I, IL-2, EL-3, EL-4, IL-5, IL-6, EL- 7, IL-8, IL-15, EL-16, EL-18, TLrIl, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF; antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (g ⁇ 39 or CD40L); TNF ⁇ converting enzyme (TACE) inhibitors; IL-I inhibitors (Interleukin-1 -converting enzyme inhibitors, DL-IRA etc.); Interleuk
  • IL-l ⁇ converting enzyme (ICE) inhibitors T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM and p55TNFRIgG (Lenercept)), sIL-lRI, sIL-lRII, sEL-6R); antiinflammatory cytokines (e.g.
  • EL-4, EL-IO, EL-11, EL-13 and TGFb Rituximab
  • IL-I TRAP MRA
  • CTLA4-Ig IL-18 BP
  • anti-EL-18 anti-EL15
  • EDEC- CE9.1/SB 210396 non-depleting primatized anti-CD4 antibody; EDEC/SmithKline; see e.g., Arthritis & Rheumatism (1995) Vol. 38, S185); DAB 486-IL-2 and/or DAB 389-D-- 2 (EL-2 fusion proteins; Seragen; see e.g., Arthritis & Rheumatism (1993) Vol.
  • Anti-Tac humanized anti-EL-2Ra; Protein Design Labs/Roche
  • EL-4 anti-inflammatory cytokine; DNAX/Schering
  • EL-IO SCH 52000; recombinant IL-IO, anti-inflammatory cytokine; DNAX/Schering
  • IL-IO and/or EL-4 agonists e.g., agonist antibodies
  • EL-IRA IL-I receptor antagonist; Synergen/Amgen
  • anakinra (Kineret®/Amgen)
  • TNF-bp/s- TNF soluble TNF binding protein; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S284; Amer.
  • zap-70 and/or lck inhibitor inhibitor of the tyrosine kinase zap-70 or lck
  • VEGF inhibitor and/or VEGF-R inhibitor inhibitors of vascular endothelial cell growth factor or vascular endothelial cell growth factor receptor; inhibitors of angiogenesis
  • TNF-convertase inhibitors anti-IL-12 antibodies; anti-EL-18 antibodies
  • interleukin-11 see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S296)
  • interleukin-13 see e.g., Arthritis & Rheumatism (1996) Vol. 39, No.
  • Exaraples of agents that can be used in combination with a TNF ⁇ antibody for the treatment of depression or treatment of depression and rheumatoid arthritis include, but are not limited to, small molecule inhibitor of KDR (ABT-123), small molecule inhibitor of Tie-2; methotrexate; prednisone; celecoxib; folic acid; hydroxychloroquine sulfate; rofecoxib; etanercept; infliximab; anakinra (Kineret ® /Amgen); lefiunomide; naproxen; valdecoxib; sulfasalazine; ibuprofen; methylprednisolone; meloxicam; methylprednisolone acetate; gold sodium thiomalate; aspirin; azathioprine; triamcinolone acetonide; propxyphene napsylate/apap; folate; nabu
  • a TNF ⁇ antibody may be administered for the treatment of depression or treatment of depression and an additional disorder, in combination with an antibiotic or antiinfective agent.
  • Antiinfective agents include those agents known in the art to treat viral, fungal, parasitic or bacterial infections.
  • the term, "antibiotic,” as used herein, refers to a chemical substance that inhibits the growth of, or kills, microorganisms. Encompassed by this term are antibiotic produced by a microorganism, as well as synthetic antibiotics ⁇ e.g., analogs) known in the art.
  • Antibiotics include, but are not limited to, clarithromycin (Biaxin ® ), ciprofloxacin (Cipro ® ), and metronidazole (Flagyl ® ).
  • the invention also includes administration of a TNF ⁇ antibody for the treatment of depression or treatment of depression and an additional disorder, in combination with a drug used to treat Crohn's disease or a Crohn 's-related disorder.
  • therapeutic agents which can be used to treat Crohn's disease include mesalamine, prednisone, azathioprine, mercaptopurine, infliximab, budesonide, sulfasalazine, methylprednisolone sod succ, diphenoxylate/atrop sulf, loperamide hydrochloride, methotrexate, omeprazole, folate, ciprofloxacin/ dextrose-water, hydrocodone bitartrate/apap, tetracycline hydrochloride, fluocinonide, metronidazole, thimerosal/boric acid, hyoscyamine sulfate, cholestyramine/sucrose, ciprof
  • the invention includes administration of a TNF ⁇ antibody for the treatment of depression or treatment of depression and an additional disorder, wherein the additional disorder is a spondyloarthropathy.
  • the invention includes the administration of a TNF inhibitor in combination with a drug used to treat spondyloarthropathies.
  • a drug used to treat spondyloarthropathies examples include nonsteroidal, anti-inflammatory drugs (NS AEDs), COX 2 inhibitors, including Celebrex ® , Vioxx ® , and Bextra ® , aand etoricoxib.
  • Physiotherapy is also commonly used to treat spondyloarthropathies, usually in conjunction with non-steoidal inflammatory drugs.
  • agents that can be used in a combination treatment with a TNF ⁇ antibody for the treatment of depression or treatment of depression and ankylosing spondylitis include but are not limited to ibuprofen, diclofenac and misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, prednisone, methotrexate, azathioprine, minocyclin, prednisone, etanercept, and infliximab.
  • the TNF ⁇ antibody of the invention is administered in combination with an additional therapeutic agent to treat psoriatic arthritis and depression.
  • agents which can be used to reduce or inhibit the symptoms of psoriatic arthritis include methotrexate; etanercept; rofecoxib; celecoxib; folic acid; sulfasalazine; naproxen; leflunomide; methylprednisolone acetate; indomethacin; hydroxychloroquine sulfate; sulindac; prednisone; betamethasone diprop augmented; infliximab; methotrexate; folate; triamcinolone acetonide; diclofenac; dimethyl sulfoxide; piroxicam; diclofenac sodium; ketoprofen; meloxicam; prednisone; methylprednisolone; nabumetone; tolmetin sodium; calcipotriene;
  • the TNF ⁇ antibody may be administered in combination with topical corticosteroids, vitamin D analogs, and topical or oral retinoids, or combinations thereof, for the treatment of psoriasis.
  • the TNF ⁇ antibody may be administered in combination with one of the following agents for the treatment of psoriasis: small molecule inhibitor of KDR (ABT-123), small molecule inhibitor of Tie-2, calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone, acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobe
  • an antibody, antibody portion may be used in combination with other agents to treat skin conditions in subjects also having depression.
  • an antibody, antibody portion, or other TNF ⁇ inhibitor of the invention is combined with PUVA therapy.
  • PUVA is a combination of psoralen (P) and long-wave ultraviolet radiation (UVA) that is used to treat many different skin conditions.
  • the antibodies, antibody portions, or other TNF ⁇ inhibitors of the invention can also be combined with pimecrolimus.
  • the antibodies of the invention are used to treat psoriasis, wherein the antibodies are administered in combination with tacrolimus.
  • tacrolimus and TNF ⁇ inhibitors are administered in combination with methotrexate and/or cyclosporine.
  • the TNF ⁇ inhibitor of the invention is administered with excimer laser treatment for treating psoriasis and depression.
  • any one of the above-mentioned therapeutic agents can be administered to a subject suffering from depression or to a subject suffering from depression and an additional disorder, in combination with the TNF ⁇ antibody.
  • the additional agents described for specific additional disorders are not limited to said disorders, but may be used in a combination therapy with aTNF ⁇ antibody for treatment of depression or depression and an additional disorder.
  • Example 1 Systemic administration of a TNFaantibody treats depression using a murine model
  • the following example demonstrates the effect of a murine antibody as an inhibitor against TNF ⁇ in the depressive-like behaviors elicited following the systemic administration of recombinant mouse TNF- ⁇ in mouse Tail Suspension Test.
  • the mouse Tail Suspension Test (mTST) is one of the most extensively used animal models of depression, and is considered to have a good predictive value for detecting antidepressant activity.
  • the model is based on the experimental procedure described by Steru et al. Psychopharmacology (1985) 85:367-370 and Steru et al. Prog. Neuro-Psychopharmacol. & Biol. Psychiat.
  • the test assesses immobility time in animals exposed to a short-term inescapable stressor (being suspended by the tail). After initial vigorous attempts to struggle and escape from the situation, the mice develop an immobile posture, which has been called behavioral despair, suggestive of a "depressive- like state", and hypothesized to reflect lowered mood or hopelessness.
  • TST is sensitive to a broad variety of antidepressant treatments, which significantly reduce the immobility period and promote the occurrence of escape-oriented behaviors in the test. For the procedure, animals were habituated to the testing room for approximately
  • mice Male Balb/c mice weighing about 20-25g (Charles River Laboratories) were used for the experiment. After habituation to the testing room, animals were assigned to two groups that were injected i.p. with either mouse Immunoglobulin G (IgG, 300 ⁇ g/mice) (Sigma, St. Louis, MO) or the murine antibody against TNF- ⁇ (ABC, Abbott Laboratories ⁇ (300 ⁇ g/mice), both dissolved in PBS solution administered in a volume of 0.25 ml / mouse. Two hours after the pretreatment, half of the animals belonging to each experimental group received a second systemic administration (i.p. injection) of the rmTNF- ⁇ (E.
  • IgG mouse Immunoglobulin G
  • AAC Abbott Laboratories ⁇
  • mice received an injection of PBS solution (0.25 ml). Behavioral testing in the mTST took place 1 hour after the second administration.
  • rmTNF- ⁇ i.p. induced depressive-like behavior as demonstrated by increased immobility time in the mTST compared to the appropriate control group (IgG + TNF- ⁇ compared to IgG + PBS) (p ⁇ 0.001).
  • Table 1 Effect of murine monoclonal antibody against TNF- ⁇ in depressive-like behaviors elicited following the systemic administration of rmTNF- ⁇ in mTST. Values represent immobility time (s) during the 6-min test in the mTST model of depression.
  • TNF ⁇ antibody i.e., adalimumab
  • TRD Treatment-Resistant Depression
  • a 9-week, randomized, double-blind, parallel group, multi-center study is conducted to explore the efficacy and safety of adalimumab compared to placebo as adjunctive therapy.
  • the study is conducted in approximately 120 patients diagnosed with major depression and having a HAM- D 24 score > 20, despite two previous adequate treatment trials with standard antidepressant medications.
  • the study consists of a screening period of approximately 7 days and a 9-week treatment period. Subjects are randomly assigned to each of the two treatment groups (adalimumab 40mg once weekly (QW) and matching placebo) in equal numbers with approximately 60 subjects per group.
  • the main inclusion criteria include the following: male or non-pregnant, non- lactating female (female subjects of childbearing potential must be using effective contraception); age between 18 and 75, inclusive, at the time of randomization; a current DSM-IV-TM primary diagnosis of major unipolar depression without psychotic features as confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID); satisfaction of the criteria for Treatment-Resistant Depression as defined by a HAM-D 24 score > 20 despite two previous adequate treatment trials with standard anti-depressant medications; a stable anti-depressant regimen for > 4 weeks; general good health; and informed consent.
  • Exclusion criteria include: history of cancer or lymphoproliferative disease; history of listeria, HIV, Hepatitis B or C, immunodeficiency, demyelinating disease or tuberculosis; poorly controlled medical condition, or any condition for which surgery or medication change is anticipated during study; recent systemic antibiotic, antiviral or antifungal treatment; positive C.
  • the mode of systemic administration can be, for example, subcutaneous injection.
  • the reference therapy is a placebo for adalimumab, systemically administered with a device, e.g., a pen device, for example, by subcutaneous injection.
  • a device e.g., a pen device
  • the duration of the study is 9 weeks, with one week double-blind placebo lead-in and 8 weeks double- blind treatment.
  • the criteria for evaluation of adalimumab for the treatment of major depression include efficacy, pharmacodynamic, and safety.
  • the primary efficacy variable is the HAM-D total score change from baseline to last study visit (day 64).
  • Other efficacy variables used to determine the efficacy of adalimumab for the treatment of major depression include HAM-A, CGI, PGI, and quality of life scores.
  • biomarkers including DNA, cytokines, metabolites and sleep quality can be explored as predictors of response.
  • a plasma sample can be banked for potential additional exploratory analyses.
  • Safety measures include vital signs, previous concomitant medication, anti-nuclear antibodies (ANA), electrocardiogram (ECG), urine toxicology, urine pregnancy, hematology/general labs, urinalysis and adverse events (AE) monitoring.
  • Treatment of depression is indicated by an improvement or remission response in the patient as indicated by the HAM-D score.
  • Statistical methods in efficacy are conducted by a maximum likelihood-based, mixed-model repeated measures analysis of HAM-D total score.
  • the model includes the fixed categorical effects of treatment, investigator, visit and treatment-by- visit interaction and the continuous fixed covarities of screening HAM-D total score and screening-by- visit interaction.
  • the primary comparison is the contrast on change from screening to the last visit of the study.
  • HAM-D change from baseline to the last observation is assessed using analysis of covariance with factors for treatment and investigator, and the screening HAM-D total score as a covariate.
  • remission HAM-D ⁇ 7

Abstract

La présente invention concerne des procédés de traitement de la dépression consistant à administrer un anticorps anti-TNF-α, tel qu'un anticorps anti-TNF-α humain.
PCT/US2006/032365 2005-08-19 2006-08-18 Procede de traitement de la depression au moyen d'un anticorps anti-tnf-alpha WO2007024705A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06801876.1A EP1924287B1 (fr) 2005-08-19 2006-08-18 Procédé de traitement de la dépression au moyen d'un anticorps anti-tnf-alpha

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70999805P 2005-08-19 2005-08-19
US60/709,998 2005-08-19

Publications (2)

Publication Number Publication Date
WO2007024705A2 true WO2007024705A2 (fr) 2007-03-01
WO2007024705A3 WO2007024705A3 (fr) 2007-09-27

Family

ID=37772215

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/032365 WO2007024705A2 (fr) 2005-08-19 2006-08-18 Procede de traitement de la depression au moyen d'un anticorps anti-tnf-alpha

Country Status (5)

Country Link
US (3) US20070041905A1 (fr)
EP (1) EP1924287B1 (fr)
KR (1) KR101373695B1 (fr)
TW (1) TWI386226B (fr)
WO (1) WO2007024705A2 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172340A3 (fr) * 2011-06-13 2013-03-07 Ith Immune Therapy Holdings Traitement de troubles mentaux
US9605070B2 (en) 2014-01-31 2017-03-28 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US9726666B2 (en) 2011-06-13 2017-08-08 Tla Targeted Immunotherapies Ab Diagnosing and treating inflammatory diseases
US9732152B2 (en) 2002-08-16 2017-08-15 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9771417B2 (en) 2014-08-07 2017-09-26 Novartis Ag Angiopoietin-like 4 antibodies and methods of use
US9988443B2 (en) 2014-08-07 2018-06-05 Novartis Ag Angiopoetin-like 4 (ANGPTL4) antibodies and methods of use
US10450288B2 (en) 2014-01-10 2019-10-22 Glaxosmithkline Intellectual Property (No. 2) Limited Hydroxy formamide derivatives and their use
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
US10669337B2 (en) 2014-07-25 2020-06-02 Cytomx Therapeutics, Inc. Bispecific anti-CD3 antibodies, bispecific activatable anti-CD3 antibodies, and methods of using the same
US10752687B2 (en) 2014-01-24 2020-08-25 Novartis Ag Antibody molecules to PD-1 and uses thereof
WO2020175954A1 (fr) * 2019-02-28 2020-09-03 (주)셀트리온 MÉTHODE DE TRAITEMENT DES MALADIES LIÉES AU TNFα
US11161906B2 (en) 2013-07-25 2021-11-02 Cytomx Therapeutics, Inc. Multispecific antibodies, multispecific activatable antibodies and methods of using the same
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies

Families Citing this family (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090382A (en) * 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
SI9720020B (en) * 1996-02-09 2001-12-31 Basf Ag Human antibodies that bind human TNF alpha
CA2868614A1 (fr) 2001-06-08 2002-12-08 Abbott Laboratories (Bermuda) Ltd. Methodes pour administrer des anticorps anti-tnf.alpha.
US20040009172A1 (en) * 2002-04-26 2004-01-15 Steven Fischkoff Use of anti-TNFalpha antibodies and another drug
NZ555692A (en) * 2002-07-19 2009-02-28 Abbott Biotech Ltd Treatment of TNF alpha related disorders
US20090280065A1 (en) * 2006-04-10 2009-11-12 Willian Mary K Uses and Compositions for Treatment of Psoriasis
MY150740A (en) * 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
TW201705980A (zh) 2004-04-09 2017-02-16 艾伯維生物技術有限責任公司 用於治療ＴＮＦα相關失調症之多重可變劑量療法
GB0414054D0 (en) 2004-06-23 2004-07-28 Owen Mumford Ltd Improvements relating to automatic injection devices
EP1807111A4 (fr) * 2004-10-08 2009-05-27 Abbott Biotech Ltd Infection a virus respiratoire syncytial (rsv)
CN101500607B (zh) 2005-05-16 2013-11-27 阿布维生物技术有限公司 TNFα抑制剂治疗腐蚀性多关节炎的用途
TW201337266A (zh) * 2005-11-01 2013-09-16 Abbott Biotech Ltd 利用生物標記診斷關節黏連脊椎炎之方法及組合物
SG170837A1 (en) 2006-04-05 2011-05-30 Abbott Biotech Ltd Antibody purification
US20080118496A1 (en) * 2006-04-10 2008-05-22 Medich John R Uses and compositions for treatment of juvenile rheumatoid arthritis
US9624295B2 (en) 2006-04-10 2017-04-18 Abbvie Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
US9399061B2 (en) * 2006-04-10 2016-07-26 Abbvie Biotechnology Ltd Methods for determining efficacy of TNF-α inhibitors for treatment of rheumatoid arthritis
US9605064B2 (en) * 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US20090317399A1 (en) * 2006-04-10 2009-12-24 Pollack Paul F Uses and compositions for treatment of CROHN'S disease
WO2007120626A2 (fr) 2006-04-10 2007-10-25 Abbott Biotechnology Ltd. Utilisations et compositions pour le traitement de la spondylarthrite ankylosante
US20080131374A1 (en) * 2006-04-19 2008-06-05 Medich John R Uses and compositions for treatment of rheumatoid arthritis
US20080311043A1 (en) * 2006-06-08 2008-12-18 Hoffman Rebecca S Uses and compositions for treatment of psoriatic arthritis
US20100021451A1 (en) 2006-06-08 2010-01-28 Wong Robert L Uses and compositions for treatment of ankylosing spondylitis
TWI527603B (zh) * 2006-06-30 2016-04-01 艾伯維生物技術有限責任公司 自動注射裝置
MX2009004351A (es) 2006-10-27 2009-05-12 Abbott Biotech Ltd Anticuerpos anti-htnfalfa cristalinos.
EP2165194A4 (fr) * 2007-05-31 2010-09-08 Abbott Lab BIOMARQUEURS PRÉDICTIFS DE LA RÉACTIVITÉ AUX INHIBITEURS TNF-alpha DANS DES TROUBLES AUTO-IMMUNS
EP2171451A4 (fr) 2007-06-11 2011-12-07 Abbott Biotech Ltd Procédés de traitement de l'arthrite idiopathique juvénile
US20090110679A1 (en) * 2007-07-13 2009-04-30 Luk-Chiu Li Methods and compositions for pulmonary administration of a TNFa inhibitor
SG183709A1 (en) 2007-08-08 2012-09-27 Abbott Lab Compositions and methods for crystallizing antibodies
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
NZ709704A (en) 2007-11-30 2017-03-31 Abbvie Biotechnology Ltd Protein formulations and methods of making same
CN101965514A (zh) * 2008-01-03 2011-02-02 艾博特生物技术有限公司 预测化合物在治疗银屑病中的长期功效
SG2013054218A (en) 2008-01-15 2014-10-30 Abbott Gmbh & Co Kg Powdered protein compositions and methods of making same
US8497122B2 (en) 2008-04-11 2013-07-30 Washington University Biomarkers for Niemann-pick C disease and related disorders
CA2722466A1 (fr) * 2008-04-29 2009-11-05 Tariq Ghayur Immunoglobulines a double domaine variable et utilisations
AU2009256250B2 (en) * 2008-06-03 2013-05-30 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
CA2725666A1 (fr) * 2008-06-03 2009-12-10 Abbott Laboratories Immunoglobulines a double domaine variable et leurs utilisations
NZ590074A (en) * 2008-07-08 2012-12-21 Abbott Lab Prostaglandin e2 dual variable domain immunoglobulins and uses thereof
WO2010048347A2 (fr) * 2008-10-21 2010-04-29 Astute Medical, Inc. Procédés et compositions pour le diagnostic et le pronostic de lésion rénale et d’insuffisance rénale
US20100233079A1 (en) * 2008-12-04 2010-09-16 Abbott Laboratories Dual Variable Domain Immunoglobulins and Uses Thereof
RU2595379C2 (ru) * 2009-04-16 2016-08-27 АббВай Биотерапеутикс Инк. АНТИТЕЛА ПРОТИВ TNF-α И ИХ ПРИМЕНЕНИЯ
TWI583418B (zh) * 2009-04-29 2017-05-21 艾伯維生物技術有限責任公司 針筒柱塞及自動注射裝置
AU2010242840B2 (en) * 2009-05-01 2014-04-17 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
JP2012526121A (ja) * 2009-05-04 2012-10-25 アボツト・バイオテクノロジー・リミテツド ヒト抗ｔｎｆアルファ抗体の安定した高蛋白質濃度製剤
UY32808A (es) * 2009-07-29 2011-02-28 Abbott Lab Inmunoglobulinas como dominio variable dual y usos de las mismas
KR20140015139A (ko) * 2009-10-15 2014-02-06 애브비 인코포레이티드 이원 가변 도메인 면역글로불린 및 이의 용도
UY32979A (es) 2009-10-28 2011-02-28 Abbott Lab Inmunoglobulinas con dominio variable dual y usos de las mismas
CN102812040A (zh) * 2009-10-30 2012-12-05 雅培制药有限公司 Sorf构建体和多基因表达
TWI619521B (zh) * 2009-12-15 2018-04-01 艾伯維生物技術有限責任公司 自動注射裝置、自動注射方法及防止不發射情況之方法
CN102167741B (zh) * 2010-02-25 2014-05-14 上海百迈博制药有限公司 一种全人源抗TNF-α单克隆抗体、其制备方法及用途
CN102167744B (zh) * 2010-02-25 2014-08-20 上海百迈博制药有限公司 一种全人源抗cd20单克隆抗体、其制备方法及用途
SI2575884T1 (sl) 2010-06-03 2018-10-30 Abbvie Biotechnology Ltd Uporabe in sestavki za zdravljenje supurativnega hidradenitisa (HS)
CA2807014A1 (fr) 2010-08-03 2012-02-09 Abbvie Inc. Immunoglobulines a double domaine variable et utilisations associees
TW201211252A (en) 2010-08-26 2012-03-16 Abbott Lab Dual variable domain immunoglobulins and uses thereof
MX344727B (es) 2010-11-11 2017-01-05 Abbvie Biotechnology Ltd Formulaciones liquidas de anticuerpos anti-tnf-alfa de alta concentracion mejoradas.
PE20141436A1 (es) 2011-01-24 2014-11-15 Abbvie Biotechnology Ltd Dispositivos de inyeccion automatica con superficies de agarre sobremoldeadas
US9133272B2 (en) 2011-03-01 2015-09-15 Amgen Inc. Bispecific binding agents
WO2012149197A2 (fr) 2011-04-27 2012-11-01 Abbott Laboratories Procédé de contrôle du profil de galactosylation de protéines exprimées de manière recombinante
US9023995B2 (en) 2011-11-16 2015-05-05 Boehringer Ingelheim International Gmbh Anti IL-36R antibodies
UY34558A (es) 2011-12-30 2013-07-31 Abbvie Inc Proteínas de unión específicas duales dirigidas contra il-13 y/o il-17
SI2830662T1 (sl) * 2012-03-29 2019-01-31 The Trustees Of Columbia University In The City Of New York Postopki zdravljenja motenj izgube las
US9334319B2 (en) 2012-04-20 2016-05-10 Abbvie Inc. Low acidic species compositions
WO2013158273A1 (fr) 2012-04-20 2013-10-24 Abbvie Inc. Procédés de modulation de la distribution de variant de lysine c-terminal
US9067990B2 (en) 2013-03-14 2015-06-30 Abbvie, Inc. Protein purification using displacement chromatography
WO2013176754A1 (fr) 2012-05-24 2013-11-28 Abbvie Inc. Nouvelle purification d'anticorps au moyen de chromatographie à interaction hydrophobe
UY34905A (es) 2012-07-12 2014-01-31 Abbvie Inc Proteínas de unión a il-1
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
KR20150043523A (ko) 2012-09-02 2015-04-22 애브비 인코포레이티드 단백질 불균일성의 제어 방법
AU2013337775B2 (en) 2012-11-01 2017-03-30 Abbvie Inc. Anti-VEGF/DLL4 dual variable domain immunoglobulins and uses thereof
US20150342946A1 (en) 2013-01-30 2015-12-03 Pharmorx Therapeutics, Inc. Treatments For Depression And Other Diseases With A Low Dose Agent
SG11201507230PA (en) 2013-03-12 2015-10-29 Abbvie Inc Human antibodies that bind human tnf-alpha and methods of preparing the same
US9017687B1 (en) 2013-10-18 2015-04-28 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
WO2014159579A1 (fr) 2013-03-14 2014-10-02 Abbvie Inc. Anticorps anti-tnfα ayant mutés et leurs procédés d'utilisation
WO2014151878A2 (fr) 2013-03-14 2014-09-25 Abbvie Inc. Procédés pour la modulation des profils de glycosylation de protéines de traitements à base de protéines recombinantes au moyen de monosaccharides et d'oligosaccharides
CN105324396A (zh) 2013-03-15 2016-02-10 艾伯维公司 针对IL-1β和/或IL-17的双重特异性结合蛋白
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
AU2014337263B2 (en) 2013-10-16 2019-12-12 Outlook Therapeutics, Inc. Buffer formulations for enhanced antibody stability
US9085618B2 (en) 2013-10-18 2015-07-21 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
US9181337B2 (en) 2013-10-18 2015-11-10 Abbvie, Inc. Modulated lysine variant species compositions and methods for producing and using the same
US8946395B1 (en) 2013-10-18 2015-02-03 Abbvie Inc. Purification of proteins using hydrophobic interaction chromatography
WO2015073884A2 (fr) 2013-11-15 2015-05-21 Abbvie, Inc. Compositions de protéines de liaison génétiquement glycomodifiées
CN103709251B (zh) * 2013-12-19 2016-04-13 江苏众红生物工程创药研究院有限公司 全人源抗cd26抗体及其应用
US10093733B2 (en) 2014-12-11 2018-10-09 Abbvie Inc. LRP-8 binding dual variable domain immunoglobulin proteins
EP3247718B1 (fr) 2015-01-21 2021-09-01 Outlook Therapeutics, Inc. Modulation de variants de charge dans une composition d'anticorps monoclonaux
HUE055000T2 (hu) 2015-02-27 2021-10-28 Dechra Ltd Étvágy stimulálása, tömegvesztés kézbentartása és anorexia kezelése kutyák és macskák esetében
EP3078675A1 (fr) 2015-04-10 2016-10-12 Ares Trading S.A. Régime de dosage à induction pour le traitement des maladies liées au tnf alpha
TW201710286A (zh) 2015-06-15 2017-03-16 艾伯維有限公司 抗ｖｅｇｆ、ｐｄｇｆ及／或其受體之結合蛋白
CN106661117B (zh) * 2015-12-30 2020-11-17 深圳先进技术研究院 IgG杂合型抗TNFα和IL-17A双特异性抗体
EP3411401A1 (fr) 2016-02-03 2018-12-12 Oncobiologics, Inc. Formulations de tampon pour améliorer la stabilité d'anticorps
JOP20190248A1 (ar) 2017-04-21 2019-10-20 Amgen Inc بروتينات ربط مولد ضد trem2 واستخداماته
BR112021016198A2 (pt) 2019-03-08 2021-11-03 Boehringer Ingelheim Int Formulações de anticorpo anti-il-36r
EP4110329A4 (fr) * 2020-02-24 2024-04-10 Yinuoke Medicine Science Tech Company Ltd Compositions et méthodes pour le traitement d'un choc cytokinique et d'un syndrome de libération de cytokines
CN113249493A (zh) * 2021-03-05 2021-08-13 浙江省血液中心 一种人血小板同种抗原***等位基因分型的实时荧光pcr方法、探针、引物及试剂盒

Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4510245A (en) 1982-11-18 1985-04-09 Chiron Corporation Adenovirus promoter system
EP0154316A2 (fr) 1984-03-06 1985-09-11 Takeda Chemical Industries, Ltd. Lymphokine chimiquement modifiée et son procédé de préparation
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
US4968615A (en) 1985-12-18 1990-11-06 Ciba-Geigy Corporation Deoxyribonucleic acid segment from a virus
EP0401384A1 (fr) 1988-12-22 1990-12-12 Kirin-Amgen, Inc. Facteur de stimulation de colonies de granulocytes modifies chimiquement
WO1991003553A1 (fr) 1989-09-05 1991-03-21 Immunex Corporation RECEPTEURS DES FACTEURS NECROSE TUMORALE α et $g(b)
WO1991017271A1 (fr) 1990-05-01 1991-11-14 Affymax Technologies N.V. Procedes de triage de banques d'adn recombine
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1992009690A2 (fr) 1990-12-03 1992-06-11 Genentech, Inc. Methode d'enrichissement pour des variantes de l'hormone de croissance avec des proprietes de liaison modifiees
WO1992015679A1 (fr) 1991-03-01 1992-09-17 Protein Engineering Corporation Phage de visualisation d'un determinant antigenique ameliore
WO1992018619A1 (fr) 1991-04-10 1992-10-29 The Scripps Research Institute Banques de recepteurs heterodimeres utilisant des phagemides
WO1992020791A1 (fr) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methode de production de chainons de paires de liaison specifique
US5168062A (en) 1985-01-30 1992-12-01 University Of Iowa Research Foundation Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
WO1993001288A1 (fr) 1991-07-08 1993-01-21 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Phagemide utile pour trier des anticorps
WO1993006213A1 (fr) 1991-09-23 1993-04-01 Medical Research Council Production d'anticorps chimeriques - une approche combinatoire
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
WO1993019751A1 (fr) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes utilisables dans le traitement des maladies inflammatoires et dans l'inhibition de la production du facteur de necrose tumorale
WO1994006476A1 (fr) 1992-09-15 1994-03-31 Immunex Corporation Procede de traitement de l'inflammation dependante du facteur necrosant des tumeurs malignes (tnf) a l'aide d'antagonistes dudit tnf
US5656272A (en) 1991-03-18 1997-08-12 New York University Medical Center Methods of treating TNF-α-mediated Crohn's disease using chimeric anti-TNF antibodies
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
US6258562B1 (en) 1996-02-09 2001-07-10 Basf Aktiengesellschaft Human antibodies that bind human TNFα
WO2002012502A2 (fr) 2000-08-07 2002-02-14 Centocor, Inc. Anticorps anti-tnf, compositions, methodes et utilisations
US6449380B1 (en) 2000-03-06 2002-09-10 Intel Corporation Method of integrating a watermark into a compressed image
US6451983B2 (en) 1989-08-07 2002-09-17 Peptech Limited Tumor necrosis factor antibodies
WO2002072636A2 (fr) 2000-12-28 2002-09-19 Altus Biologics Inc. Cristaux d'anticorps entiers et fragments d'anticorps et methodes de fabrication et d'utilisation associees
US20030049256A1 (en) 1999-02-24 2003-03-13 Tobinick Edward Lewis Cytokine antagonists for neurological and neuropsychiatric disorders
US6593458B1 (en) 1989-08-07 2003-07-15 Peptech Limited Tumor necrosis factor peptide binding antibodies
WO2004009776A2 (fr) 2002-07-19 2004-01-29 Abbott Biotechnology Ltd. Traitement de troubles en relation avec le tnf$g(a)
US20050095246A1 (en) 2003-10-24 2005-05-05 Medtronic, Inc. Techniques to treat neurological disorders by attenuating the production of pro-inflammatory mediators
US9702219B2 (en) 2014-10-01 2017-07-11 Halliburton Energy Services, Inc. Polymerizable ionic liquids for use in subterranean formation operations
US10411705B1 (en) 2018-09-28 2019-09-10 Arm Limited System, method and apparatus for electronic circuit

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5672347A (en) * 1984-07-05 1997-09-30 Genentech, Inc. Tumor necrosis factor antagonists and their use
DE3631229A1 (de) * 1986-09-13 1988-03-24 Basf Ag Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung
FR2651130B1 (fr) * 1989-08-23 1991-12-13 Roussel Uclaf Sequence d'oligonucleotides anti-sens, anti-arn message du tnf alpha, procede de preparation, application a titre de medicaments et compositions pharmaceutiques.
GB8928874D0 (en) * 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US5859205A (en) * 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
GB9014932D0 (en) * 1990-07-05 1990-08-22 Celltech Ltd Recombinant dna product and method
US5994510A (en) * 1990-12-21 1999-11-30 Celltech Therapeutics Limited Recombinant antibodies specific for TNFα
US20060246073A1 (en) * 1991-03-18 2006-11-02 Knight David M Anti-TNF antibodies and peptides of human tumor necrosis factor
US6277969B1 (en) * 1991-03-18 2001-08-21 New York University Anti-TNF antibodies and peptides of human tumor necrosis factor
US20070298040A1 (en) * 1991-03-18 2007-12-27 Centocor, Inc. Methods of treating seronegative arthropathy with anti-TNF antibodies
US20040120952A1 (en) * 2000-08-07 2004-06-24 Centocor, Inc Anti-TNF antibodies and peptides of human tumor necrosis factor
US6270766B1 (en) * 1992-10-08 2001-08-07 The Kennedy Institute Of Rheumatology Anti-TNF antibodies and methotrexate in the treatment of arthritis and crohn's disease
PT614984E (pt) * 1993-03-05 2001-12-28 Bayer Ag Anticorpos humanos anti-tnf
NZ278607A (en) * 1994-02-07 1999-05-28 Knoll Ag Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above
CA2190586A1 (fr) * 1994-05-17 1995-11-23 Scott E. Plevy Procedes pour depister la maladie de crohn a l'aide d'alleles microsatellites du facteur de necrose tumorale
US6861053B1 (en) * 1999-08-11 2005-03-01 Cedars-Sinai Medical Center Methods of diagnosing or treating irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth
JPH11507843A (ja) 1996-03-28 1999-07-13 ザ・ジョンズ・ホプキンス・ユニバーシティー タンパク質の可溶性二価および多価ヘテロ二量体類縁体
US5916748A (en) * 1996-04-12 1999-06-29 Cedars-Sinai Medical Center Method of diagnosing a clinical subtype of crohn's disease with features of ulcerative colitis
EA002174B1 (ru) * 1997-07-03 2002-02-28 Пфайзер Инк. Фармацевтические композиции, содержащие гемисульфат элетриптана и кофеин
US20030113318A1 (en) * 1999-02-24 2003-06-19 Tobinick Edward Lewis TNF inhibition for the treatment of pre-menstrual syndrome and primary dysmenorrhea
EP1041072B1 (fr) * 1999-03-31 2003-07-16 Pfizer Products Inc. Acides dioxocyclopentylhydroxamiques
US20050249735A1 (en) * 2000-08-07 2005-11-10 Centocor, Inc. Methods of treating ankylosing spondylitis using anti-TNF antibodies and peptides of human tumor necrosis factor
US20060018907A1 (en) * 2000-08-07 2006-01-26 Centocor, Inc. Anti-TNF antibodies and peptides of human tumor necrosis factor
CA2868614A1 (fr) * 2001-06-08 2002-12-08 Abbott Laboratories (Bermuda) Ltd. Methodes pour administrer des anticorps anti-tnf.alpha.
US20040033228A1 (en) * 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
US20040052790A1 (en) * 2002-09-18 2004-03-18 Advanced Biotherapy, Inc. Treatment of schizophrenia
MY150740A (en) * 2002-10-24 2014-02-28 Abbvie Biotechnology Ltd Low dose methods for treating disorders in which tnf? activity is detrimental
DE602004025100D1 (de) * 2003-05-23 2010-03-04 Novo Nordisk Healthcare Ag Stabilisierung von proteinen in lösung
KR20070010046A (ko) * 2004-04-06 2007-01-19 제넨테크, 인크. Ｄｒ5 항체 및 그의 용도
TW201705980A (zh) * 2004-04-09 2017-02-16 艾伯維生物技術有限責任公司 用於治療ＴＮＦα相關失調症之多重可變劑量療法
US20050240443A1 (en) * 2004-04-23 2005-10-27 Ester Salman Method and system for accepting data related to a patient
US7313442B2 (en) * 2004-04-30 2007-12-25 Advanced Neuromodulation Systems, Inc. Method of treating mood disorders and/or anxiety disorders by brain stimulation
US20080045949A1 (en) * 2005-06-17 2008-02-21 Hunt Margaret M Method of treating degenerative spinal disorders
JP2009514977A (ja) * 2005-11-08 2009-04-09 メダレックス インコーポレーティッド 免疫刺激性治療用抗体による治療に付随した腸炎に対するＴＮＦ−α遮断剤処置法

Patent Citations (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4510245A (en) 1982-11-18 1985-04-09 Chiron Corporation Adenovirus promoter system
US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
EP0154316A2 (fr) 1984-03-06 1985-09-11 Takeda Chemical Industries, Ltd. Lymphokine chimiquement modifiée et son procédé de préparation
US5168062A (en) 1985-01-30 1992-12-01 University Of Iowa Research Foundation Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence
US4968615A (en) 1985-12-18 1990-11-06 Ciba-Geigy Corporation Deoxyribonucleic acid segment from a virus
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
EP0401384A1 (fr) 1988-12-22 1990-12-12 Kirin-Amgen, Inc. Facteur de stimulation de colonies de granulocytes modifies chimiquement
US6593458B1 (en) 1989-08-07 2003-07-15 Peptech Limited Tumor necrosis factor peptide binding antibodies
US6498237B2 (en) 1989-08-07 2002-12-24 Peptech Limited Tumor necrosis factor antibodies
US6451983B2 (en) 1989-08-07 2002-09-17 Peptech Limited Tumor necrosis factor antibodies
WO1991003553A1 (fr) 1989-09-05 1991-03-21 Immunex Corporation RECEPTEURS DES FACTEURS NECROSE TUMORALE α et $g(b)
WO1991017271A1 (fr) 1990-05-01 1991-11-14 Affymax Technologies N.V. Procedes de triage de banques d'adn recombine
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1992020791A1 (fr) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methode de production de chainons de paires de liaison specifique
WO1992009690A2 (fr) 1990-12-03 1992-06-11 Genentech, Inc. Methode d'enrichissement pour des variantes de l'hormone de croissance avec des proprietes de liaison modifiees
WO1992015679A1 (fr) 1991-03-01 1992-09-17 Protein Engineering Corporation Phage de visualisation d'un determinant antigenique ameliore
US5656272A (en) 1991-03-18 1997-08-12 New York University Medical Center Methods of treating TNF-α-mediated Crohn's disease using chimeric anti-TNF antibodies
WO1992018619A1 (fr) 1991-04-10 1992-10-29 The Scripps Research Institute Banques de recepteurs heterodimeres utilisant des phagemides
WO1993001288A1 (fr) 1991-07-08 1993-01-21 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Phagemide utile pour trier des anticorps
WO1993006213A1 (fr) 1991-09-23 1993-04-01 Medical Research Council Production d'anticorps chimeriques - une approche combinatoire
WO1993019751A1 (fr) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes utilisables dans le traitement des maladies inflammatoires et dans l'inhibition de la production du facteur de necrose tumorale
WO1994006476A1 (fr) 1992-09-15 1994-03-31 Immunex Corporation Procede de traitement de l'inflammation dependante du facteur necrosant des tumeurs malignes (tnf) a l'aide d'antagonistes dudit tnf
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
US6258562B1 (en) 1996-02-09 2001-07-10 Basf Aktiengesellschaft Human antibodies that bind human TNFα
US6509015B1 (en) 1996-02-09 2003-01-21 Basf Aktiengesellschaft Human antibodies that bind human TNFa
US20030049256A1 (en) 1999-02-24 2003-03-13 Tobinick Edward Lewis Cytokine antagonists for neurological and neuropsychiatric disorders
US6449380B1 (en) 2000-03-06 2002-09-10 Intel Corporation Method of integrating a watermark into a compressed image
WO2002012502A2 (fr) 2000-08-07 2002-02-14 Centocor, Inc. Anticorps anti-tnf, compositions, methodes et utilisations
WO2002072636A2 (fr) 2000-12-28 2002-09-19 Altus Biologics Inc. Cristaux d'anticorps entiers et fragments d'anticorps et methodes de fabrication et d'utilisation associees
WO2004009776A2 (fr) 2002-07-19 2004-01-29 Abbott Biotechnology Ltd. Traitement de troubles en relation avec le tnf$g(a)
US20050095246A1 (en) 2003-10-24 2005-05-05 Medtronic, Inc. Techniques to treat neurological disorders by attenuating the production of pro-inflammatory mediators
US9702219B2 (en) 2014-10-01 2017-07-11 Halliburton Energy Services, Inc. Polymerizable ionic liquids for use in subterranean formation operations
US10411705B1 (en) 2018-09-28 2019-09-10 Arm Limited System, method and apparatus for electronic circuit

Non-Patent Citations (79)

* Cited by examiner, † Cited by third party
Title
"Current Protocols in Molecular Biology", 1989, GREENE PUBLISHING ASSOCIATES
"Diagnostic and Statistical Manual of Mental Disorders-Text Revision", 2000, WASHINGTON: AMERICAN PSYCHIATRIC ASSOCIATION
"Diagnostic and Statistical Manual of Mental Disorders-Text Revision.", 2000, AMERICAN PSYCHIATRIC ASSOCIATION.
"Molecular Cloning; A Laboratory Manual", 1989, COLD SPRING HARBOR
"Sustained and Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC.
ACTA PSYCHIATRICA SCANDINAVICA, vol. 106, 2002, pages 252 - 64
ACTA PSYCHIATRICA SCANDINAVICA, vol. 67, 1983, pages 361 - 370
AMER. J. PHYSIOL. - HEART AND CIRCULATORY PHYSIOLOGY, vol. 268, 1995, pages 37 - 42
ARCHIVES OF GENERAL PSYCHIATRY, vol. 4, 1961, pages 561 - 571
ARTHRITIS & RHEUMATISM, vol. 36, 1993, pages 1223
ARTHRITIS & RHEUMATISM, vol. 38, 1995, pages 185
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 120
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 282
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 284
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 296
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 308
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 81
ARTHRITIS & RHEUMATISM, vol. 39, no. 9, 1996, pages 82
BARBAS ET AL., PNAS, vol. 88, 1991, pages 7978 - 7982
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
BOSS, M.A.; WOOD, C. R., IMMUNOLOGY TODAY, vol. 6, 1985, pages 12 - 13
BRITISH JOURNAL OF MEDICAL PSYCHOLOGY, vol. 32, 1959, pages 50 - 55
BRITISH JOURNAL OF PSYCHIATRY, vol. 134, 1979, pages 382 - 389
CANFIELD, S.M.; S.L. MORRISON, J. EXP. MED., vol. 173, 1991, pages 1483 - 1491
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
COX, J.P.L. ET AL.: "A Directory of Human Germ-line V78 Segments Reveals a Strong Bias in their Usage", EUR. J. IMMUNOL., vol. 24, 1994, pages 827 - 836, XP003004702, DOI: doi:10.1002/eji.1830240409
DAVIS, J.M. ET AL., BIOCHEMISTRY, vol. 26, 1987, pages 1322 - 1326
ELLIOT, M.J. ET AL., LANCET, vol. 344, 1994, pages 1105 - 1110
ELLIOTT, M.J. ET AL., LANCET, vol. 344, 1994, pages 1125 - 1127
FOCUS ON GROWTH FACTORS, vol. 3, 1992, pages 4 - 10
FUCHS ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 1370 - 1372
GARRARD ET AL., BIOLTECLMOLOGY, vol. 2, 1991, pages 1373 - 1377
GOEDDEL: "Gene Expression Technology: Methods in Enzymology", vol. 185, 1990, ACADEMIC PRESS
GRAM ET AL., PNAS, vol. 89, 1992, pages 3576 - 3580
GRIFFITHS ET AL., EMBO J, vol. 12, 1993, pages 725 - 734
GUY W: "Clinical Global Impressions ECDEU Assessment Manual for Psychopharmacology", 1976, NATIONAL INSTITUTE OF MENTAL HEALTH, pages: 218 - 222
HAWKINS ET AL., J MOL BIOL, vol. 226, 1992, pages 889 - 896
HAY ET AL., HUM ANTIBOD HYBRIDOMAS, vol. 3, 1992, pages 81 - 85
HOLLIGER, P. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 6444 - 6448
HOOGENBOOM ET AL., NUC ACID RES, vol. 19, 1991, pages 4133 - 4137
HUSE ET AL., SCIENCE, vol. 246, 1989, pages 1275 - 1281
HUSTON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883
JOHNNSON ET AL., ANAL. BIOCLAEM., vol. 198, 1991, pages 268
JOHNSSON ET AL., J. MOL. RECOGNIT., vol. 8, 1995, pages 125
JONES, E.Y. ET AL., NATURE, vol. 338, 1989, pages 225 - 228
JONSSON ET AL., ANN. BIOL. CLIN., vol. 51, 1993, pages 19
JÖNSSON ET AL., BIOTECHNIQUES, vol. 11, 1991, pages 620 - 627
JOURNAL OF AFFECTIVE DISORDERS, vol. 66, 2001, pages 159 - 164
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, vol. 23, 1960, pages 56 - 62
KABAT, E.A. ET AL.: "Sequences of Proteins of Immunological Interest", 1991, NIH PUBLICATION NO. 91-3242
KABAT, E.A. ET AL.: "Sequences of Proteizzs of Immunological Interest", 1991, NIH PUBLICATION NO. 91-3242
KOSTELNY, J. IMMUNOL., vol. 148, 1992, pages 1547 - 1553
LANQUILLON ET AL., NEUROPSYCHOPHARMACOLOGY, vol. 22, 2000, pages 370 - 379
LEVINE, J. ET AL., NEUROPSYCHOBIOLOGY, vol. 40, 1999, pages 171 - 6
LUND, J. ET AL., J. OFLMMUNOL., vol. 147, 1991, pages 2657 - 2662
MCCAFFERTY ET AL., NATURE, vol. 348, 1990, pages 552 - 554
MIKOVA ET AL., EUR NEUROPSYCHOPHARMACOL, vol. 11, 2001, pages 203 - 8
MIKOVA ET AL., EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol. 11, 2001, pages 203 - 208
PENNICA, D. ET AL., NATURE, vol. 312, 1984, pages 724 - 729
PENNINX ET AL., BIOL PSYCHIATRY, vol. 54, 2003, pages 566 - 572
PENNINX, BIOL PSYCHIATRY, vol. 54, 2003, pages 566 - 72
POLJAK, R.J. ET AL., STRUCTURE, vol. 2, 1994, pages 1121 - 1123
R.J. KAUFMAN; P.A. SHARP, MOL. BIOL., vol. 159, 1982, pages 601 - 621
RANKIN,EC ET AL., BR. J. RHEUMATOL., vol. 34, 1995, pages 334 - 342
See also references of EP1924287A4
SLUZEWSKA, A. ET AL.: "Indicators of immune activation has been identified in major depression", PSYCHIATRY RES, vol. 64, 1996, pages 161 - 7
SONGSIVILAI; LACHMANN, CLIN. EXP. IMINUNOL., vol. 79, 1990, pages 315 - 321
SOUERY ET AL., J CLIN PSYCHIATRY, vol. 67, 2006, pages 16 - 22
STERU ET AL., PROG. NEURO-PSYCHOPHARMACOL. & BIOL. PSYCHIAT, vol. 11, 1987, pages 659 - 671
STERU ET AL., PSYCHOPHARMACOLOGY, vol. 85, 1985, pages 367 - 370
TAYLOR, LD. ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 6287
THASE, HARV REV PSYCHIATRY., vol. 13, no. 5, 2005, pages 257 - 71
TOMLINSON, I.M. ET AL.: "The Repertoire of Human Germline VH Sequences Reveals about Fifty Groups of VH Segments with Different Hypervariable Loops", J. MOL. BIOL., vol. 227, 1992, pages 776 - 798, XP024020607, DOI: doi:10.1016/0022-2836(92)90223-7
TRZONKOWSLD ET AL., BRAIN BEHAV IMMUN, vol. 18, 2004, pages 135 - 48
TUGLU ET AL., PSYCHOPHAMZACOLOGY (BERL, vol. 170, 2003, pages 429 - 33
TUGLU ET AL., PSYCHOPHARMACOLOGY (BERL, vol. 170, 2003, pages 429 - 33
TUGLU ET AL., PSYCHOPHARMACOLOGY, vol. 170, 2003, pages 429 - 433
URLAUB; CHASIN, PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216 - 4220
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 546

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9750808B2 (en) 2002-08-16 2017-09-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US9738714B2 (en) 2002-08-16 2017-08-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9732152B2 (en) 2002-08-16 2017-08-15 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US10401357B2 (en) 2011-06-13 2019-09-03 Tla Targeted Immunotherapies Ab Treating cancer
US10502736B2 (en) 2011-06-13 2019-12-10 Tla Targeted Immunotherapies Ab Treating multiple sclerosis
US9726666B2 (en) 2011-06-13 2017-08-08 Tla Targeted Immunotherapies Ab Diagnosing and treating inflammatory diseases
WO2012172340A3 (fr) * 2011-06-13 2013-03-07 Ith Immune Therapy Holdings Traitement de troubles mentaux
US10408832B2 (en) 2011-06-13 2019-09-10 Tla Targeted Immunotherapies Ab Treating mental disorders
US10422800B2 (en) 2011-06-13 2019-09-24 Tla Targeted Immunotherapies Ab Treating respiratory conditions
US10429385B2 (en) 2011-06-13 2019-10-01 Tla Targeted Immunotherapies Ab Treating conditions associated with sepsis
US10451620B2 (en) 2011-06-13 2019-10-22 Tla Targeted Immunotherapies Ab Treating conditions associated with metabolic syndrome
US11161906B2 (en) 2013-07-25 2021-11-02 Cytomx Therapeutics, Inc. Multispecific antibodies, multispecific activatable antibodies and methods of using the same
US11708412B2 (en) 2013-09-26 2023-07-25 Novartis Ag Methods for treating hematologic cancers
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
US10450288B2 (en) 2014-01-10 2019-10-22 Glaxosmithkline Intellectual Property (No. 2) Limited Hydroxy formamide derivatives and their use
US10752687B2 (en) 2014-01-24 2020-08-25 Novartis Ag Antibody molecules to PD-1 and uses thereof
US11827704B2 (en) 2014-01-24 2023-11-28 Novartis Ag Antibody molecules to PD-1 and uses thereof
US10981990B2 (en) 2014-01-31 2021-04-20 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US9605070B2 (en) 2014-01-31 2017-03-28 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US10472419B2 (en) 2014-01-31 2019-11-12 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US9884913B2 (en) 2014-01-31 2018-02-06 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US11155620B2 (en) 2014-01-31 2021-10-26 Novartis Ag Method of detecting TIM-3 using antibody molecules to TIM-3
US10669337B2 (en) 2014-07-25 2020-06-02 Cytomx Therapeutics, Inc. Bispecific anti-CD3 antibodies, bispecific activatable anti-CD3 antibodies, and methods of using the same
US11802158B2 (en) 2014-07-25 2023-10-31 Cytomx Therapeutics, Inc. Bispecific anti-CD3 antibodies, bispecific activatable anti-CD3 antibodies, and methods of using the same
US9771417B2 (en) 2014-08-07 2017-09-26 Novartis Ag Angiopoietin-like 4 antibodies and methods of use
US10577411B2 (en) 2014-08-07 2020-03-03 Novartis Ag Angiopoietin-like 4 antibodies and methods of use
US9988443B2 (en) 2014-08-07 2018-06-05 Novartis Ag Angiopoetin-like 4 (ANGPTL4) antibodies and methods of use
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies
WO2020175954A1 (fr) * 2019-02-28 2020-09-03 (주)셀트리온 MÉTHODE DE TRAITEMENT DES MALADIES LIÉES AU TNFα

Also Published As

Publication number Publication date
KR101373695B1 (ko) 2014-03-17
EP1924287A4 (fr) 2010-12-15
TW200738270A (en) 2007-10-16
KR20080040720A (ko) 2008-05-08
US20070081996A1 (en) 2007-04-12
TWI386226B (zh) 2013-02-21
EP1924287B1 (fr) 2015-01-14
US20140296493A1 (en) 2014-10-02
US20070041905A1 (en) 2007-02-22
EP1924287A2 (fr) 2008-05-28
WO2007024705A3 (fr) 2007-09-27

Similar Documents

Publication Publication Date Title
EP1924287B1 (fr) Procédé de traitement de la dépression au moyen d'un anticorps anti-tnf-alpha
US9669093B2 (en) Methods for treating juvenile idiopathic arthritis
US8926975B2 (en) Method of treating ankylosing spondylitis
US8986693B1 (en) Use of TNFα inhibitor for treatment of psoriasis
JP2014132008A (ja) 骨損失を治療するための方法及び組成物
WO2007120651A2 (fr) Utilisation et compositions pour le traitement de l'arthrite rhumatoïde juvénile
CA2564435A1 (fr) Methodes de controle et de traitement des troubles intestinaux
EP2666479A2 (fr) Utilisations et compositions pour le traitement de l'arthrite rhumatoïde juvénile
AU2016256831B2 (en) Use of TNF inhibitor for treatment of erosive polyarthritis
AU2016256831A1 (en) Use of TNF inhibitor for treatment of erosive polyarthritis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2006801876

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006801876

Country of ref document: EP

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)